Piperidinyl-methyl-purineamines as NSD2 inhibitors and anti-cancer agents

ABSTRACT

The present invention provides a compound of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or an enantiomer, an enantiomeric mixture, or a pharmaceutically acceptable salt thereof; wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds for treating a disease or condition mediated by nuclear SET domain-containing protein 2 (NSD2).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international (PCT) patentapplication no. PCT/IB2020/057602, filed Aug. 12, 2020, which claims thebenefit of and priority to PCT/CN2019/100542, filed Aug. 14, 2019; thecontents of these applications are incorporated by reference herein intheir entirety.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods forinhibiting the nuclear SET domain-containing protein 2 (NSD2).

BACKGROUND OF THE INVENTION

The nuclear receptor-binding SET domain protein 2 (NSD2), also known asWolf-Hirschhorn syndrome candidate 1 (WHSC1) or multiple myeloma SETdomain (MMSET) is an epigenetic modifier, and is believed to have adriving role in oncogenesis. Both NSD2 overexpression and pointmutations that increase its catalytic activity are associated withseveral human cancers. (Coussens et al., J. Biol. Chem. 293, 13750-13654(2018).

NSD2 is dysregulated by the t(4;14)(p16.3;q32.3) translocation inapproximately 15% of multiple myeloma (MM) cases. Increased expressionof NSD2 in t(4;14)+MM cell lines is associated with increased levels ofH3K36me2 and reciprocally decreased levels of H3K27me3. Such correlationsuggests a causal relationship between NSD2 histone methyltransferase(HMT) activity and the MM oncogene.

High expression of the NSD2 protein has been demonstrated in differenthuman cancer types, including bladder, brain, gastrointestinal, lung,liver, ovary, skin, uterus, breast, prostrate and glioblastoma.(Coussens et al., supra; Ezponda et al., Oncogene 32:2882-2890 (2013)).Notably, NSD2 is among the most frequently mutated genes in pediatriccancer genomes. The NSD2 SET domain variant, E1099K, was identified inboth acute lymphoblastic leukemia tumors and cell lines with increasedH3K36me2 that lack the t(4;14) translocation. Sequence results of >1000pediatric cancer genomes, representing 21 different cancers, revealedthe E1099K variant in 14% of t(12;21) ETV6-RUNX1 containing acutelymphoblastic leukemia (ALL). NSD2 is also among the most frequentlymutated genes found in mantle cell lymphoma tumors, where both E1099Kand T1150A variants are observed. The E1099K variant has also beenreported in chronic lymphocytic leukemia (CLL), lung and stomachcancers. (Coussens et al., supra). In general, NSD2 upregulation isassociated with aggressive tumor behavior and poor prognosis. (Ezpondaet al., supra).

NSD2 is a promising target for cancer therapy, and there remains a needfor selective inhibitors of NSD2.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that inhibit NSD2; andcompositions and methods for treating or preventing a disease orcondition mediated by NSD2.

In one aspect, the invention provides a compound of Formula (I):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof; wherein:

A is N or CR⁹ wherein R⁹ is hydrogen or halo;

L is a bond or C₁₋₄ alkylene;

R¹ is H; or

R¹ and R² together with NH forms a 5-8 membered heterocyclyl containing1-2 heteroatoms selected from N, O and S as ring members; wherein said5-8 membered heterocyclyl is unsubstituted or substituted by an oxosubstituent;

R² is selected from the group consisting of:

(i) hydrogen, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, -hydroxyC₁₋₆ alkylene,-hydroxyhaloC₁₋₆ alkylene, —C₁₋₆ alkoxyC₁₋₆alkylene, -haloC₁₋₆alkoxyC₁₋₆ alkylene or —C₃₋₈ cycloalkoxy(C₁₋₆ alkyl);

(ii) cyano; -cyanoC₁₋₆ alkylene; —C₁₋₆ alkylthioC₁₋₆alkyl; —C₂₋₆alkenyl; -haloC₂₋₆ alkenyl; —C₂₋₆ alkynyl; —C₁₋₄ alkylSOC₁₋₄alkyl; —C₁₋₄alkylSO₂C₁₋₄alkyl; —SO₂R⁸ or —C(C₁₋₄ alkyl)=N—O(C₁₋₄ alkyl);

(iii) —C₁₋₄alkylcarbonyl; —(CR^(a)R^(b))_(p)—C(═O)—OR¹⁰; or—C(═O)—(CR^(a)R^(b))_(g)R¹¹—; wherein R¹¹ is C₃₋₇ cycloalkyl, 5-6membered heterocyclyl or 5-6 membered heteroaryl, each of which isindependently unsubstituted or substituted with C₁₋₆ alkyl or C₁₋₆alkoxy;

(iv) —(CR^(a)R^(b)), C(═O)—NR¹²R¹³ wherein R¹² is hydrogen or C₁₋₆alkyl; R¹³ is hydrogen, —C₁₋₆ alkyl or a 5-6 membered heterocyclic ring;or R¹² and R¹³ together form a 5-6 membered heterocyclic ring; whereinsaid 5-6 membered heterocyclic ring is unsubstituted or substituted withC₁₋₄ alkyl;

(v) 5-6 membered heterocyclylC₀₋₆alkyl or 5-6 memberedheterocyclyl(haloC₁₋₄ alkyl) wherein each said heterocyclyl radical isunsubstituted or substituted by oxo; and

(vi) 5-9 membered heteroarylC₀₋₆alkyl or 5-9 memberedheteroaryl(haloC₁₋₄alkyl), wherein each said heteroaryl radical isunsubstituted or substituted by —C₁₋₄ alkyl, -haloC₁₋₄ alkyl,-hydroxyC₁₋₄ alkylene, —C₁₋₄ alkoxy,-haloC₁₋₄ alkoxy, halo, hydroxy,cyano, oxido, -aminocarbonylC₀₋₆alkyl, —C₁₋₄alkylaminocarbonylC₀₋₆alkyl,-diC₁₋₄alkylaminocarbonylC₀₋₆alkyl or —C₃₋₇ cycloalkyl;

R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R^(6a) and R^(6b) areindependently hydrogen, halo, cyano, hydroxyl, —C₁₋₆ alkyl, -haloC₁₋₆alkyl, -hydroxyC₁₋₆ alkylene, —C₁₋₆ alkoxy, —C₁₋₆alkoxyC₁₋₆alkylene,-haloC₁₋₆ alkoxyC₁₋₆ alkylene, -hydroxyhaloC₁₋₆ alkylene, aryl,—C(═O)—OR¹⁴ or —(CR^(a)R^(b))_(s)—C(═O)—NR¹⁵R¹⁶; or

R^(3a) and R^(3b), R^(4a) and R^(4b), R^(5a) and R^(5b) or R^(6a) andR^(6b) forms an oxo substituent;

R⁷ is H, —C₁₋₄alkoxy, halo or C₁₋₄ alkyl; or 3-8 membered heterocyclyl,which is unsubstituted or substituted by halo;

R⁸ is C₃₋₈ cycloalkyl(C₀₋₆alkyl); 4-6 membered heterocyclylC₀₋₆alkylcomprising 1-3 heteroatoms selected from N, O and S; aryl or 5-9membered heteroarylC₀₋₆alkyl comprising 1-3 heteroatoms selected from N,O and S; wherein R⁸ is unsubstituted or substituted by 1-3 R¹⁷;

R¹⁷ is halo, hydroxy, cyano, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy,-haloC₁₋₆ alkoxy, —NR^(a)C(═O)CR^(c)═C(R^(c))₂ or—(CR^(a)R^(b))_(t)—NR^(a)—C(═O)—R¹⁸;

R^(a), R^(b), R^(c), R¹⁰, R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen or—C₁₋₄ alkyl;

R¹⁸ is —C₁₋₄ alkyl or —C₁₋₄ haloalkyl; and

p, q, r, s and t are independently 0-4.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) or sub-formulae thereof, or a pharmaceutically acceptable saltthereof; and one or more pharmaceutically acceptable carriers.

In yet another aspect, the invention provides a combination, inparticular a pharmaceutical combination, comprising a therapeuticallyeffective amount of a compound of Formula (I) or sub-formulae thereof,or a pharmaceutically acceptable salt thereof; and one or moretherapeutically active agent(s).

The compounds of the invention, alone or in combination with one or moretherapeutically active agent(s), can be used for treating or preventinga disease or condition mediated by NSD2; and more particularly whereinthe disease or condition is characterized by overexpression or undesiredupregulation of NSD2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions and methods for treating orpreventing a disease or condition mediated by NSD2.

Definitions

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “—C₁₋₆alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to six carbon atoms,and which is attached to the rest of the molecule by a single bond. Theterm “C₁₋₄alkyl” is to be construed accordingly. Examples of C₁₋₆alkylinclude, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl).

As used herein, the term “—C₂₋₆alkenyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing at least one double bond, having from two to sixcarbon atoms, which is attached to the rest of the molecule by a singlebond. The term “C₂₋₄alkenyl” is to be construed accordingly. Examples ofC₂₋₆alkenyl include, but are not limited to, ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, pent-4-enyl and penta-1,4-dienyl.

As used herein, the term “—C₂₋₆alkynyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing at least one triple bond, having from two to sixcarbon atoms, and which is attached to the rest of the molecule by asingle bond. The term “C₂₋₄alkynyl” is to be construed accordingly.Examples of C₂₋₆alkynyl include, but are not limited to, ethynyl,prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl and penta-1,4-diynyl.

As used herein, the term “—C₁₋₆alkoxy” refers to a radical of theformula —OR_(a) where R_(a) is a C₁₋₆alkyl radical as generally definedabove. Examples of C₁₋₆alkoxy include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term “—C₁₋₆alkoxyC₁₋₆alkylene” refers to a radicalof the formula —R_(a)—O—R_(a) where each R^(a) is independently aC₁₋₆alkyl radical as defined above. The oxygen atom may be bonded to anycarbon atom in either alkyl radical. Examples of C₁₋₆alkoxy C₁₋₆alkylinclude, but are not limited to, methoxy-methyl, methoxy-ethyl,ethoxy-ethyl, 1-ethoxy-propyl and 2-methoxy-butyl.

As used herein, the term “—C₁₋₄alkylcarbonyl” refers to a radical of theformula —C(═O)—R_(a) where R_(a) is a C₁₋₄alkyl radical as definedabove.

As used herein, the term “—C₁₋₄alkylthioC₁₋₄alkyl” refers to a radicalof the formula

—R_(a)—S—R_(a) where each R_(a) is independently a C₁₋₄ alkyl radical asdefined above.

As used herein, the term “-hydroxyC₁₋₆alkylene” refers to a C₁₋₆alkylradical as defined above, wherein one of the hydrogen atoms of theC₁₋₆alkyl radical is replaced by OH. Examples of hydroxyC₁₋₆alkylinclude, but are not limited to, ethan-1-olyl, 2-methylpropan-1-olyl,hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and5-hydroxy-pentyl.

As used herein, the term “-aminocarbonylC₁₋₆alkyl” refers to a radicalof the formula

—R_(a)—C(═O)—NH₂ wherein R_(a) is a single bond or a C₁₋₆alkyl radicalas defined above.

As used herein, the term “—C₁₋₄alkylaminocarbonylC₁₋₆alkyl” refers to aradical of the formula

—R_(a1)—C(═O)—NH—R_(a2) where R_(a1) is a single bond or a C₁₋₆ alkylradical as defined above; and R_(a2) is a C₁₋₆alkyl radical as definedabove.

As used herein, the term “-diC₁₋₄alkylaminocarbonylC₁₋₆alkyl” refers toa radical of the formula —R_(a1)—C(═O)—N(R_(a2))—R_(a2) where R_(a1) isa single bond or a C₁₋₆alkyl radical as defined above; and each R_(a2)is a C₁₋₄alkyl radical as defined above, and may be the same ordifferent.

As used herein, the term “—C₃₋₈cycloalkylC₀₋₆alkyl” refers to a stablemonocyclic saturated hydrocarbon radical consisting solely of carbon andhydrogen atoms, having from three to eight carbon atoms, and which isattached to the rest of the molecule by a single bond (i.e.,C₃₋₈cycloalkyl) or by a C₁₋₆alkyl radical as defined above. The terms“C₃₋₇cycloalkyl” and “C₃₋₇ cycloalkylC₀₋₄alkyl” are to be construedaccordingly. Examples of C₃₋₈cycloalkylC₁₋₆alkyl include, but are notlimited to, cyclopropyl, cyclopropyl-methyl, cyclobutyl,cyclobutyl-ethyl, cyclopentyl, cyclopentyl-propyl, cyclohexyl,cyclohepty and cyclooctyl.

As used herein, the term “—C₃₋₈cycloalkoxyC₁₋₆alkyl” refers to a radicalof the formula —R_(a)—O—R_(b) wherein R_(a) is independently a C₁₋₆alkylradical as defined above and R_(b) is a C₃₋₈cycloalkyl as defined above.Examples of C₃₋₈cycloalkoxyC₁₋₆alkyl include but are not limited tocyclopropoxymethyl and cyclobutoxymethyl.

“Halo” refers to bromo, chloro, fluoro or iodo.

As used herein, the term “-haloC₁₋₆alkyl” refers to a C₁₋₆alkyl radical,as defined above, substituted by one or more halo radicals, as definedabove. Examples of haloC₁₋₆alkyl include, but are not limited to,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and1,4,4-trifluorobutan-2-yl. The term “haloC₁₋₄alkyl” is to be construedaccordingly.

As used herein, the term “-haloC₁₋₆alkoxyC₁₋₄alkylene” refers to aradical of the formula —R_(a1)—O—R_(a2) wherein R_(a1) is a C₁₋₆alkylradical as defined above; and R_(a2) is a haloC₁₋₆alkyl as definedabove. Examples of haloC₁₋₆alkoxyC₁₋₄alkyl include but are not limitedto (difluoromethoxyl)methyl, (2,2,2-trifluoroethoxy)methyl and(2,2-difluoroethoxy)methyl.

As used herein, the term “-hydroxylhaloC₁₋₆alkylene” refers to ahaloC₁₋₆alkyl radical, as defined above, substituted by one or morehydroxyl radicals. Examples of hydroxylhaloC₁₋₆alkyl include but are notlimited to, 2,2-difluoroethan-1-olyl; 2-fluoroethan-1-olyl; and2,2,2-trifluoroethan-1-olyl.

As used herein, the term “-cyanoC₁₋₆ alkylene” refers to a radical ofthe formula —R_(a)—CN, where R_(a) is a C₁₋₄alkyl radical as definedabove.

As used herein, the term “-haloC₂₋₆alkenyl” refers to a C₂₋₆alkenylradical, as defined above, substituted by one or more halo radicals, asdefined above.

As used herein, the term “heterocyclyl” or “heterocyclic” refers to astable 4-7 membered non-aromatic monocyclic ring radical comprising 1,2, or 3, heteroatoms individually selected from nitrogen, oxygen andsulfur. The heterocyclyl radical may be bonded via a carbon atom orheteroatom. The term “5-6 membered heterocyclyl” is to be construedaccordingly. Examples of heterocyclyl include, but are not limited to,azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl,tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl ormorpholinyl or perhydroazepinyl.

As used herein, the term “heterocyclylC₁₋₆alkyl” refers to aheterocyclic ring as defined above which is attached to the rest of themolecule by a single bond or by a C₁₋₆alkyl radical as defined above.

As used herein, the term “heteroaryl” refers to a 5-9 membered aromaticmonocyclic or fused ring radical comprising 1, 2, 3 or 4 heteroatomsindividually selected from nitrogen, oxygen and sulfur. The heteroarylradical may be bonded via a carbon atom or heteroatom. The term “5-6membered heteroaryl” is to be construed accordingly. Examples of 5-6membered monocyclic heteroaryls include, but are not limited to, furyl,pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl,pyrimidyl or pyridyl. Examples of fused heteroaryls include but are notlimited to 9-membered heteroaryls such as benzofuranyl;2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl;benzo[d][1,3]dioxol-5-yl; imidazo[1,2-a]pyridinyl;pyrazolo[1,5-a]pyridineyl; 1H-indazolyl and 1H-benzo[d]-imidazolyl.

As used herein, the term “heteroarylC₁₋₆alkyl” refers to a heteroarylring as defined above which is attached to the rest of the molecule by asingle bond or by a C₁₋₆alkyl radical as defined above.

As used herein, the term “heteroaryl(haloC₁₋₄alkyl)” refers to aheteroaryl ring as defined above which is attached to the rest of themolecule by a haloC₁₋₄alkyl as defined above. An illustrative example ofan heteroaryl(haloC₁₋₄alkyl) is fluoro(pyridin-2-yl)methyl.

“IC₅₀”, as used herein, refers to the molar concentration of aninhibitor or modulator that produces 50% inhibition.

“Protected derivatives”, as used herein, refers to derivatives ofinhibitors in which a reactive site or sites are blocked with protectinggroups. Protected derivatives are useful in the preparation ofinhibitors or in themselves may be active as inhibitors. Examples ofprotected group includes, but are not limited to, acetyl,tetrahydropyran, methoxymethyl ether, β-methoxyethoxymethyl ether,ρ-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether,carbobenzyloxy, benzyl, tert-butoxycarbonyl, ρ-methoxyphenyl,9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes,methylesters, benzyl esters, tert-butyl esters, and silyl esters. Acomprehensive list of suitable protecting groups can be found in T.W.Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, Inc. 1999.

The term “disease or condition mediated by nuclear SET domain-containingprotein 2 (NSD2)” refers to a disease or condition that is directly orindirectly regulated by NSD2.

As used herein, the term “subject” refers to mammals, primates (e.g.,humans, male or female), dogs, rabbits, guinea pigs, pigs, rats andmice. In certain embodiments, the subject is a primate. In yet otherembodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers to alleviating or ameliorating the disease ordisorder (i.e., slowing or arresting the development of the disease orat least one of the clinical symptoms thereof); or alleviating orameliorating at least one physical parameter or biomarker associatedwith the disease or disorder, including those which may not bediscernible to the patient.

As used herein, the term “prevent”, “preventing” or “prevention” of anydisease or disorder refers to the prophylactic treatment of the diseaseor disorder; or delaying the onset or progression of the disease ordisorder

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a therapeutically effective amount” of acompound of the present invention refers to an amount of the compound ofthe present invention that will elicit the biological or medicalresponse of a subject, for example, reduction or inhibition of an enzymeor a protein activity, or ameliorate symptoms, alleviate conditions,slow or delay disease progression, or prevent a disease, etc.

As used herein, the term “anti-cancer agent” or antineoplastic agent,refers to a therapeutic agent that is useful for treating or controllingthe growth of cancerous cells.

As used herein, the term “anti-inflammatory agent” refers to atherapeutic agent that reduces inflammation (redness, swelling and/orpain) in the body. Anti-inflammatory agents block certain substances inthe body that cause inflammation.

As used herein, the term “pharmaceutical composition” refers to acompound of the invention, or a pharmaceutically acceptable saltthereof, together with at least one pharmaceutically acceptable carrier,in a form suitable for oral or parenteral administration.

As used herein, the term “pharmaceutically acceptable carrier” refers toa substance useful in the preparation or use of a pharmaceuticalcomposition and includes, for example, suitable diluents, solvents,dispersion media, surfactants, antioxidants, preservatives, isotonicagents, buffering agents, emulsifiers, absorption delaying agents,salts, drug stabilizers, binders, excipients, disintegration agents,lubricants, wetting agents, sweetening agents, flavoring agents, dyes,and combinations thereof, as would be known to those skilled in the art(see, for example, Remington The Science and Practice of Pharmacy,22^(nd) Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides novel compounds that inhibit NSD2; andcompositions and methods for treating or preventing a condition mediatedby NSD2.

Various enumerated embodiments of the invention are described herein.Features specified in each embodiment may be combined with otherspecified features to provide further embodiments of the presentinvention.

Embodiment 1. A compound of Formula (I), or an enantiomer, anenantiomeric mixture, or a pharmaceutically acceptable salt thereof; asdescribed above.

Embodiment 2. A compound of Formula (I) according to Embodiment 1, or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein A is N.

Embodiment 3. A compound of Formula (I) according to Embodiment 1 or 2,or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof; wherein

R^(3a) is hydrogen or halo; and R^(3b) is hydrogen, halo, -hydroxyl,—C₁₋₆ alkoxy or cyano; or

R^(4a) is hydrogen or halo; and R^(4b) is hydrogen, halo,—C₁₋₆alkoxyC₁₋₆alkylene, —C₁₋₆ alkyl or -haloC₁₋₆ alkyl; or

R^(5a) is hydrogen and R^(5b) is hydrogen or —C₁₋₆ alkyl; or

R^(5a) and R^(5b) together form an oxo substituent.

Embodiment 4. A compound of Formula (I) according to any one ofEmbodiments 1-3, or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein

R^(6a) is hydrogen or halo;

R^(6b) is hydrogen, -haloC₁₋₆ alkoxyC₁₋₆ alkylene, -hydroxyC₁₋₆alkylene, -hydroxyhaloC₁₋₆ alkylene, carboxyl, phenyl or—(CR^(a)R^(b))_(t)—C(O)—NR¹⁵R¹⁶;

R^(a), R^(b), R¹⁵ and R¹⁶ are independently hydrogen or —C₁₋₄ alkyl; and

t is 0-1; or

R^(6a) and R^(6b) together form an oxo substituent.

Embodiment 5. A compound of Formula (I) according to any one ofEmbodiments 1-4, or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein R⁷ is H, —C₁₋₄ alkoxyor halo.

Embodiment 6. A compound of Formula (I) according to any one ofEmbodiments 1-5, or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein R¹, R^(3a), R^(3b),R^(4a), R^(4b), R^(5a), R^(5b), R^(6a), R^(6b) and R⁷ are hydrogen.

Embodiment 7. A compound of Formula (I) according to Embodiment 1,wherein said compound is a compound of Formula (II):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof.

Embodiment 8. A compound of Formula (II) according to Embodiment 7,wherein said compound is a compound of Formula (IIA):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof.

Embodiment 9. A compound according to any one of Embodiments 1-8, or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof, wherein R² is hydrogen, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl,-hydroxyC₁₋₆ alkylene, -hydroxyhaloC₁₋₆ alkylene, —C₁₋₆alkoxyC₁₋₆alkylene, -haloC₁₋₆ alkoxyC₁₋₆ alkylene or —C₃₋₈ cycloalkoxy(C₁₋₆alkyl).

Embodiment 10. A compound according to any one of Embodiments 1-8 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is —C₁₋₄ alkylcarbonyl;

—(CR^(a)R^(b))_(p)—C(O)—OR¹⁰ wherein R¹⁰ is hydrogen or —C₁₋₄ alkyl;—C(O)—(CR^(a)R^(b))_(q)—R¹¹ wherein R¹¹ is C₃₋₆ cycloalkyl, 5-6 memberedheterocyclyl or 5-6 membered heteroaryl, each of which is independentlyunsubstituted or substituted with —C₁₋₆ alkyl or —C₁₋₆ alkoxy; or—(CR^(a)R^(b))_(r)—C(O)—NR¹²R¹³; wherein

R¹² is hydrogen or —C₁₋₆ alkyl;

R¹³ is hydrogen, —C₁₋₆ alkyl or a 5-6 membered heterocyclic ring; or

R¹² and R¹³ together form a 5-6 membered heterocyclic ring; wherein said5-6 membered heterocyclic ring is unsubstituted or substituted with—C₁₋₄ alkyl; and

R^(a), R^(b) and R¹¹ are independently hydrogen or —C₁₋₄alkyl; and

p, q and r are independently 0-2.

Embodiment 11. A compound according to any one of Embodiments 1-8 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is selected from the group:

-   pyridin-2-yl, (pyridin-2-yl)methyl or (pyridin-2-yl)ethyl, wherein    said pyridin-2-yl is independently unsubstituted or substituted with    1-2 —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, hydroxyl,-   -hydroxyC₁₋₄ alkylene, cyano, —C₁₋₄alkoxy, —C₁₋₆alkoxyC₁₋₆alkylene,    -haloC₁₋₄ alkoxy, halo or —C₃₋₇ cycloalkyl;-   thiazol-4-yl, thiazol-2-ylmethyl, oxazol-2-yl, oxazol-2-ylmethyl,    pyridazin-3-yl, pyridazin-3-ylmethyl, pyrazin-2-yl,    pyrazin-2-ylmethyl, pyrimidin-4-yl, pyrimidin-4-ylmethyl, each of    which is independently unsubstituted or substituted with —C₁₋₄ alkyl    or halo;-   1H-pyrazol-3-yl, (1H-pyrazol-3-yl)methyl, 1-methyl-1H-pyrazol-4-yl,    (1,2,3-triazol-4-yl), isoxazol-3-yl, each of which is independently    unsubstituted or substituted with —C₁₋₄ alkyl, halo or —C₃₋₇    cycloalkyl;-   1,4-dioxan-2-yl;-   pyridin-2 (1H)-onyl; and-   pyridin-1-oxide-2-yl.

Embodiment 12. A compound according to any one of Embodiment 1-11 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is cyclopropyl; cyclobutyl; cyclohexyl orazetidinyl.

Embodiment 13. A compound according to any one of Embodiment 1-11 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is 2,3-dihydrobenzofuran-5-yl;1,3-dihydroisobenzofuran-5-yl; benzo[d][1,3]dioxol-5-yl;imidazo[1,2-a]pyridin-6-yl or pyrazolo[1,5-a]pyridine-6-yl.

Embodiment 14. A compound according to any one of Embodiment 1-13 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is pyridyl, unsubstituted or substituted with1-2 halo, —C₁₋₆ alkyl or —C₁₋₆ alkoxy; 1H-indazol-5-yl unsubstituted orsubstituted with 1-2 halo or —C₁₋₆ alkyl; or 1H-benzo[d]-imidazol-6-ylunsubstituted or substituted with —C₁₋₆ alkyl.

Embodiment 15. A compound according to any one of Embodiment 1-13 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is phenyl substituted with 1-3 R¹⁷;

-   -   R¹⁷ is halo, hydroxy, cyano, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆        alkoxy, -haloC₁₋₆ alkoxy, —NR^(d)C(O)CR^(d)═C(R^(d))₂ or        —(CR^(a)R^(b))_(t)—NR^(d)—C(O)R¹R⁸;    -   R^(a), R^(b) and R^(d) are independently hydrogen or —C₁₋₄        alkyl;    -   R¹⁸ is —C₁₋₄ haloalkyl; and    -   t is 0-1.

Embodiment 16. A compound according to any one of Embodiment 1-13 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is phenyl substituted with 1-3 R¹⁷; and R¹⁷ ishalo, hydroxy, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy or

-haloC₁₋₆ alkoxy.

Embodiment 17. A compound of Formula (II)

-   -   or an enantiomer, an enantiomeric mixture, or a pharmaceutically        acceptable salt thereof;    -   wherein:    -   R² is hydrogen, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, -hydroxyC₁₋₆        alkylene, -hydroxyhaloC₁₋₆ alkylene, —C₁₋₆alkoxyC₁₋₆alkylene,        -haloC₁₋₆ alkoxyC₁₋₆ alkylene or —C₃₋₈ cycloalkoxy(C₁₋₆ alkyl);    -   R⁸ is phenyl substituted with 1-3 R¹⁷; and    -   R¹⁷ is halo, hydroxy, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy        or -haloC₁₋₆ alkoxy.

Embodiment 18. A compound of Formula (II) according to Embodiment 17,wherein said compound is a compound of Formula (IIA):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof.

Embodiment 19. A compound according to any one of Embodiments 1-18 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is hydrogen; 2,2-difluoroethyl;2-methyl-propan-1-olyl; ethan-1-olyl; 2,2-difluoroethan-1-olyl;2-fluoroethan-1-olyl; 2,2,2-trifluoroethan-1-olyl; difluoromethoxyl; or2,2,2-trifluoroethoxyl.

Embodiment 20. A compound according to any one of Embodiments 1-18 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R²

Embodiment 21. A compound according to any one of Embodiments 1-20,wherein said compound is a compound from Table 2; or an enantiomer, anenantiomeric mixture, or a pharmaceutically acceptable salt thereof.

Embodiment 22. The compound according to Embodiment 21, wherein saidcompound is selected from the group consisting of:

-   1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;    and-   1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;-   or an enantiomer, an enantiomeric mixture, or a pharmaceutically    acceptable salt thereof.

Embodiment 23. The compound according to Embodiment 22, wherein saidcompound is in the (R) configuration, (S) configuration, or a mixturethereof.

Embodiment 24. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 25. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 26. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 27. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 28. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 29. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 30. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 31. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 32. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 33. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 34. The compound according to Embodiment 1, wherein saidcompound is(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof. Alternatively, thecompound is(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol,or a pharmaceutically acceptable salt thereof.

Embodiment 35. A pharmaceutical composition comprising a compoundaccording to any one of Embodiments 1-34 and one or morepharmaceutically acceptable carrier.

Embodiment 36. A combination comprising a compound according to any oneof Embodiments 1-34 and one or more additional therapeutically activeagent.

Embodiment 37. The combination according to Embodiment 36, wherein saidone or more additional therapeutically active agent is an anti-canceragent, an analgesic, an anti-inflammatory agent, or a combinationthereof.

Embodiment 38. A compound according to any one of Embodiments 1-34 andoptionally in combination with a second therapeutic agent, for use intreating a disease or condition mediated by nuclear SETdomain-containing protein 2 (NSD)2.

Embodiment 39. The compound according to Embodiment 38, wherein saidsecond therapeutic agent is an anti-cancer agent, an analgesic, ananti-inflammatory agent or a combination thereof.

Embodiment 40. Use of a compound according to any one of Embodiments1-34 and optionally in combination with a second therapeutic agent, inthe manufacture of a medicament for a disease or condition mediated byNSD2.

Embodiment 41. A method for treating a disease or condition mediated bynuclear SET domain-containing protein 2 (NSD2), comprising administeringto a subject in need thereof, a therapeutically effective amount of acompound according to any one of Embodiments 1-34 and optionally incombination with a second therapeutic agent; thereby treating saiddisease or condition mediated by NSD2.

Embodiment 42. A method for treating a disease or condition that benefitfrom or is treatable by inhibition of nuclear SET domain-containingprotein 2 (NSD2), comprising administering to a subject in need thereof,a therapeutically effective amount of a compound according to any one ofEmbodiments 1-34 and optionally in combination with a second therapeuticagent; thereby treating said disease or condition that benefit from oris treatable by inhibition by NSD2.

Embodiment 43. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is breast cancer,cervical cancer, skin cancer (particularly squamous cell carcinoma),ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lungcancer, hepatocellular carcinoma, head and neck cancer, peripheral nervesheath tumor, osteosarcoma multiple myeloma, neuroblastoma, leukemia(particularly acute lymphoblastic leukemia), non-Hodgkin's lymphoma(particularly mantle cell lymphoma), or pulmonary arterial hypertension.

Embodiment 44. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is lung cancer.

Embodiment 45. The method according to Embodiment 44, wherein said lungcancer is small cell or non-small cell lung cancer.

Embodiment 46. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is leukemia.

Embodiment 47. The method according to Embodiment 46, wherein saidleukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia(AML), chronic myeloid leukemia (CML) or chronic myelomonocytic leukemia(CMML).

Embodiment 48. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is skin cancer.

Embodiment 49. The method according to Embodiment 48, wherein said skincancer is melanoma, basal cell carcinoma or squamous cell carcinoma.

Embodiment 50. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is lymphoma.

Embodiment 51. The method according to Embodiment 50, wherein saidlymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

Embodiment 52. The method according to Embodiment 50, wherein saidlymphoma is mantle cell lymphoma or diffuse large B cell lymphoma.

Embodiment 53. The method according to Embodiment 41 or 42, wherein saiddisease or condition mediated by NSD2, or said disease or condition thatbenefit from or is treatable by inhibition of NSD2, is myeloma.

Embodiment 54. A method according to any one of Embodiment 41-53,wherein said compound is administered orally.

Unless specified otherwise, the term “compounds of the presentinvention” or “compound of the present invention” refers to compounds ofFormula (I) subformulae thereof, and exemplified compounds, and saltsthereof, as well as all stereoisomers (including diastereoisomers andenantiomers), rotamers, tautomers and isotopically labeled compounds(including deuterium substitutions), as well as inherently formedmoieties.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, for example as pure opticalisomers, or as stereoisomer mixtures, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. The present invention is meant to include all such possiblestereoisomers, including racemic mixtures, diasteriomeric mixtures andoptically pure forms. Optically active (R)- and (S)-stereoisomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. Substituents at atoms with unsaturated doublebonds may, if possible, be present in cis-(Z)- or trans-(E)-form. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible stereoisomers, rotamers,atropisomers, tautomers or mixtures thereof, for example, assubstantially pure geometric (cis or trans) stereoisomers,diastereomers, optical isomers (antipodes), racemates or mixturesthereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of compounds of the present invention or ofintermediates can be resolved into the optical antipodes by knownmethods, e.g., by separation of the diastereomeric salts thereof,obtained with an optically active acid or base, and liberating theoptically active acidic or basic compound. In particular, a basic moietymay thus be employed to resolve the compounds of the present inventioninto their optical antipodes, e.g., by fractional crystallization of asalt formed with an optically active acid, e.g., tartaric acid,dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.Racemic compounds of the present invention or racemic intermediates canalso be resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Isotopes that can be incorporated intocompounds of the invention include, for example, isotopes of hydrogen.

Further, incorporation of certain isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index ortolerability. It is understood that deuterium in this context isregarded as a substituent of a compound of Formula (I) or sub-formulaethereof. The concentration of deuterium, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor” as used hereinmeans the ratio between the isotopic abundance and the natural abundanceof a specified isotope. If a substituent in a compound of this inventionis denoted as being deuterium, such compound has an isotopic enrichmentfactor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom), at least4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation). Itshould be understood that the term “isotopic enrichment factor” can beapplied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I respectively. Accordingly itshould be understood that the invention includes compounds thatincorporate one or more of any of the aforementioned isotopes, includingfor example, radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically-labeled compounds ofFormula (I) or sub-formulae thereof can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying examplesusing an appropriate isotopically-labeled reagents in place of thenon-labeled reagent previously employed.

The compounds of the present invention are either obtained in the freeform, as a salt thereof. As used herein, the terms “salt” or “salts”refers to an acid addition or base addition salt of a compound of theinvention. “Salts” include in particular “pharmaceutical acceptablesalts”. The term “pharmaceutically acceptable salts” refers to saltsthat retain the biological effectiveness and properties of the compoundsof this invention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike. Certain organic amines include isopropylamine, benzathine,cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazineand tromethamine.

In another aspect, the present invention provides compounds of thepresent invention in acetate, ascorbate, adipate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride,chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate,gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate,hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate,malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate,naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate,sulfosalicylate, sulfate, tartrate, tosylate trifenatate,trifluoroacetate or xinafoate salt form.

Processes for Making Compounds of the Invention

All methods described herein can be performed in any suitable order,unless otherwise indicated or otherwise clearly contradicted by context.

Compounds of Formula (I) can be prepared as generally illustrated inScheme 1, wherein R¹, R², R³, . . . are as defined above. As depicted inScheme 1, Boc protected 3-CN or 3-CO₂Et piperidine undergoes SN2 or SNArreaction in the presence of strong bases (eg. NaHMDS) and a electrophilecontaining R₂ to generate compound 2 or 2′ with quaternary center, whichwas further hydrolyzed to corresponding carboxylic acid 3 or primaryamide 3′ either in basic conditions (eg. LiOH) or oxidative hydrolysisconditions (eg. H2O2, NaOH). Acid 3 or amide 3′ further undergoesCurtius or Hofmann rearrangement to generate protected quaternary amine4. After selective Boc de-protection, piperidine 5 reacts withfluorinated pyridine 6 in the presence of organic bases (eg. DIPEA)under heat to yield coupling product 7. Ester 7 is further reduced tobenzylic alcohol 8 by mild reducing agent (eg. NaBH4, LiCl), whichundergoes Mistunobu reaction with Boc protected adenine Intermediate Bto provide compound 9. After deprotection under acidic or hydrogenationconditions, chiral target molecule 10 is yielded followed by SFCseparation.

The invention further includes any variant of the present processes; forexample, wherein an intermediate product obtainable at any stage thereofis used as starting material and the remaining steps are carried out;wherein starting materials are formed in situ under the reactionconditions; or wherein the reaction components are used in the form oftheir salts or optically pure material. Compounds of the invention andintermediates can also be converted into each other according to methodsgenerally known to those skilled in the art.

Pharmacology and Utility

In one aspect, the invention provides compounds of Formula (I) orsubformulae thereof, or a pharmaceutically acceptable salt thereof, thatare useful for therapy; particularly, for treating or preventing adisease or condition that is mediated by NSD2.

In another aspect, the invention provides the use of a compound ofFormula (I) or subformulae thereof, or a pharmaceutically acceptablesalt thereof, for treating a disease or condition that benefit from oris treatable by inhibition of NSD2; and for the manufacture of amedicament for treating a disease or condition that is treatable byinhibition of NSD2.

Examples of diseases or conditions that are mediated by NDS2, or thatbenefit from or are treatable by inhibition of NSD2, include but is notlimited to breast cancer, cervical cancer, skin cancer (particularlyskin squamous cell carcinoma), ovarian cancer, gastric cancer, prostatecancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, headand neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiplemyeloma, neuroblastoma, leukemia (particularly acute lymphoblasticleukemia), non-Hodgkin's lymphoma (particularly mantle cell lymphoma),and pulmonary arterial hypertension.

Pharmaceutical Compositions, Dosage and Administration

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In a further embodiment, the composition comprises at least twopharmaceutically acceptable carriers, such as those described herein.The pharmaceutical composition can be formulated for particular routesof administration such as oral administration, parenteral administration(e.g. by injection, infusion, transdermal or topical administration),and rectal administration. Topical administration may also pertain toinhalation or intranasal application. The pharmaceutical compositions ofthe present invention can be made up in a solid form (including, withoutlimitation, capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including, without limitation,solutions, suspensions or emulsions). Tablets may be either film coatedor enteric coated according to methods known in the art. Typically, thepharmaceutical compositions are tablets or gelatin capsules comprisingthe active ingredient together with one or more of:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and

e) absorbents, colorants, flavors and sweeteners.

In another aspect, the compounds of the present invention are combinedwith other therapeutic agents, such as other anti-cancer agents,anti-allergic agents, anti-nausea agents (or anti-emetics), painrelievers, cytoprotective agents, and combinations thereof.

In one embodiment, the other therapeutic agent is an anti-cancer agentor chemo-therapeutic agent. Examples of anit-cancer agents consideredfor use in combination therapies of the invention include but are notlimited erlotinib, bortezomib, fulvestrant, sunitib imatinib mesylate,letrozole, finasunate, platins such as oxaliplatin, carboplatin, andcisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib,lonafamib, sorafenib, gefitinib, capmtothecin, topotecan, bryostatin,adezelesin, anthracyclin, carzelesin, bizelesin, dolastatin,auristatins, duocarmycin, eleutherobin, taxols such as paclitaxel ordocetaxel, cyclophasphamide, doxorubicin, vincristine, prednisone orprednisolone, other alkylating agents such as mechlorethamine,chlorambucil, and ifosfamide, antimetabolites such as azathioprine ormercaptopurine, other microtubule inhibitors (vinca alkaloids likevincristine, vinblastine, vinorelbine and vindesine, as well astaxanes), podophyllotoxins (etoposide, teniposide, etoposide phosphate,and epipodophyllotoxins), topoisomerase inhibitors, other cytotoxinssuch as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab,epirubicin, bleomycin, plicamycin, mitomycin, as well as otheranticancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab,adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab,apolizumab, bavituximab, belimumab, bivatuzumab mertansine,blinatumomab, brentuximab vedotin, cantuzumab mertansine, catumazomab,cetuximab, citatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan,conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab,edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab,farletuzumab, figitumumab, fresolimumab, galiximab, gembatumumabvedotin, gemtuzumab, ibritumomab tiuxetan, inotuzumab ozogamicin,intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab,lintuzumab, lucatumumab, lumilisimab, mapatumumab, matuzumab,milatuzumab, mitumomab, nacolomab tafenatox, naptumomab estafenatox,necitumumab, nimotuzumab, ofatumumab, olaratumab, oportuzumab monatox,oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab,ramucirumab, rilotumumab, robatumumab, rituximab, sibrotuzumab,tacatuzumab tetraxetan, taplitumomab paptox, tenatumomab, ticilimumab,tigatuzumab, tositumomab or ¹³¹I-tositumomab, trastuzumab, tremelimumab,tuocotuzumab celmoleukin, veltuzumab, visilizumab, volocixumab,votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR,EMD72000, lor-t1, MDX-220, MRA, H-11 scFv, huJ591, TriGem, TriAb, R3,MT-201, G-250, ACA-125, Onyvax-105, CD:-960, Cea-Vac, BrevaRex AR54,IMC-1C11, GlioMab-H, ING-1, anti-LCG MAbs, MT-103, KSB-303, Therex,KW2871, anti-HMI.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb,Prostate Cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), andantibody-drug conjugates comprising any of the above agents (especiallyauristatins MMAE and MMAF, maytansinoids like DM-1, calicheamycins, orvarious cytotoxins).

In another embodiment, the compounds of the invention are combined withanother therapeutic agent selected from anastrozole (ARIMIDEX),bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan(MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®),carmustine (BiCNU®), chlorambucil (LEUKERAN®), cisplatin (PLATINOL®),cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®),cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposomeinjection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin(actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®),daunorubicin citrate liposome injection (DAUNOXOME®), dexamethasone,docetaxel (TAXOTERE®), doxorubicin hydrochloride (ADRIAMYCIN®, RUBEX®),etoposide (VEPESID®), fludarabine phosphate (FLUDARA®), 5-fluorouracil(ADRUCIL®, EFUDEX®), flutamide (EULEXIN®), tezacitibine, gemcitabine(difluorodeoxycitidine), hydroxyurea (HYDREA®), idarubicin (IDAMYCIN®),ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine(PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®),gemtuzumab ozogamicin (MYLOTARG™), paclitaxel (TAXOL®), nab-paclitaxel(ABRAXANE®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®),teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®),topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine(VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®).

In another embodiment, the compounds of the present invention arecombined with another therapeutic agent capable of inhibiting BRAF, MEK,CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combinationthereof. In a particular embodiment, the compounds of the presentinvention are combined with another therapeutic agent selected fromvemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991,panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib,lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus,BMK120, BYL719 or CLR457, or a combination thereof.

In another embodiment, the therapeutic agent for use with the compoundsof the present invention is selected based on the disease or conditionthat is being treated. For example, in the treatment of melanoma, theother therapeutic agent may be selected from aldesleukin (e.g.,PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinantinterferon alfa-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g.,MEKINIST®), peginterferon alfa-2b (e.g., PEGINTRON®, SYLATRON™),vemurafenib (e.g., ZELBORAF®)), and ipilimumab (e.g., YERVOY®).

For the treatment of ovarian cancer, the other therapeutic agent may beselected from doxorubicin hydrochloride (Adriamycin®), carboplatin(PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin(PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposome (DOXIL®,DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®),topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).

For the treatment of thyroid cancer, the other therapeutic agent may beselected from doxorubicin hydrochloride (Adriamycin®),cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).

For the treatment of colon cancer, the other therapeutic may be selectedfrom fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab(AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine(XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorincalcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab(VECTIBIX®), and ziv-aflibercept (ZALTRAP®).

For the treatment of lung cancer, the other therapeutic may be selectedfrom methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®,Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxelalbumin-stabilized nanoparticle formulation (ABRAXANE®), afatinibdimaleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab(AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®,PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride(TARCEVA®), gefitinib (IRESSA®) and gemcitabine hydrochloride (GEMZAR®).

For the treatment of pancreatic cancer, the other therapeutic agent maybe selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®),erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®),and mitomycin or mitomycin C (MITOZYTREX™, MUTAMYCIN®).

For the treatment of cervical cancer, the other therapeutic agent may beselected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®,PLATINOL-AQ®) and topotecan hydrochloride (HYCAMTIN®).

For the treatment of head and neck cancer, the other therapeutic agentmay be selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEXPFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®,EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®),cisplatin (PLATINOL®, PLATINOL-AQ®) and docetaxel (TAXOTERE®).

For the treatment of leukemia, including chronic myelomonocytic leukemia(CMML), the other therapeutic agent can be selected from bosutinib(BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine(CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate(GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®) and omacetaxinemepesuccinate (SYNRIBO®).

In another aspect, the present invention provides pharmaceuticalcompositions comprising at least one compound of the present invention(e.g., a compound of Formula (I) or a sub-formulae theref) or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier suitable for administration to ahuman or animal subject, either alone or together with other anti-canceragents.

In combination therapies, compositions will either be formulatedtogether as a combination therapeutic, or as separate compositions. Thecompound of the invention and the other therapeutic agent may bemanufactured and/or formulated by the same or different manufacturers.The structure of therapeutic agents identified by code numbers, genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The other therapeuticagents, which can be used in combination with a compound of the presentinvention, can be prepared and administered as described in the art,such as in the documents cited above.

Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above. Thepharmaceutical composition or combination of the present invention canbe in unit dosage of about 0.5-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease. The above-cited dosageproperties are demonstrable in vitro and in vivo tests usingadvantageously mammals, e.g., mice, rats, dogs, monkeys or isolatedorgans, tissues and preparations thereof. The compounds of the presentinvention can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution.

In another aspect, the present invention provides methods of treatinghuman or animal subjects suffering from a cellular proliferativedisease, such as cancer, comprising administering to the subject atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt thereof, either alone or incombination with other anti-cancer agents. In combination therapy, thecompound of the present invention and other anti-cancer agent(s) may beadministered either simultaneously, concurrently or sequentially with nospecific time limits, wherein such administration providestherapeutically effective levels of the two compounds in the body of thepatient. Moreover, the compound of the invention and the othertherapeutic may be brought together into a combination therapy: (i)prior to release of the combination product to physicians (e.g. in thecase of a kit comprising the compound of the invention and the othertherapeutic agent); (ii) by the physician themselves (or under theguidance of the physician) shortly before administration; (iii) in thepatient themselves, e.g. during sequential administration of thecompound of the invention and the other therapeutic agent.

In one embodiment, the compound of the present invention and the otheranti-cancer agent(s) is generally administered sequentially in any orderby infusion or orally. The dosing regimen may vary depending upon thestage of the disease, physical fitness of the patient, safety profilesof the individual drugs, and tolerance of the individual drugs, as wellas other criteria well-known to the attending physician and medicalpractitioner(s) administering the combination. The compound of thepresent invention and other anti-cancer agent(s) may be administeredwithin minutes of each other, hours, days, or even weeks apart dependingupon the particular cycle being used for treatment. In addition, thecycle could include administration of one drug more often than the otherduring the treatment cycle and at different doses per administration ofthe drug.

In yet another aspect, compounds of the present invention may becombined with other anti-cancer agents, anti-allergic agents,anti-nausea agents (or anti-emetics), pain relievers, cytoprotectiveagents, and combinations thereof.

In some instances, patients may experience allergic reactions to thecompounds of the present invention and/or other anti-cancer agent(s)during or after administration. Therefore, anti-allergic agents may beadministered to minimize the risk of an allergic reaction. Suitableanti-allergic agents include corticosteroids, such as dexamethasone(e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone(also known as cortisone, hydrocortisone sodium succinate,hydrocortisone sodium phosphate; e.g., ALA-CORT®, hydrocortisonephosphate, Solu-CORTEF®, HYDROCORT Acetate® and LANACORT®), prednisolone(e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED® and PRELONE®), prednisone(e.g., DELTASONE®, LIQUID RED®, METICORTEN® and ORASONE®),methylprednisolone (also known as 6-methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate; e.g.,DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL® and SOLU-MEDROL®);antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine,and cyproheptadine; and bronchodilators, such as the beta-adrenergicreceptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline(BRETHINE®).

In other instances, patients may experience nausea during and afteradministration of the compound of the present invention and/or otheranti-cancer agent(s). Therefore, anti-emetics may be administered inpreventing nausea (upper stomach) and vomiting. Suitable anti-emeticsinclude aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl(KYTRIL®), lorazepam (ATIVAN®. dexamethasone (DECADRON®),prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), andcombinations thereof.

In yet other instances, medication to alleviate the pain experiencedduring the treatment period is prescribed to make the patient morecomfortable. Common over-the-counter analgesics, such TYLENOL®, areoften used. Opioid analgesic drugs such as hydrocodone/paracetamol orhydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH®or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphonehydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also usefulfor moderate or severe pain.

Furthermore, cytoprotective agents (such as neuroprotectants,free-radical scavengers, cardioprotectors, anthracycline extravasationneutralizers, nutrients and the like) may be used as an adjunct therapyto protect normal cells from treatment toxicity and to limit organtoxicities. Suitable cytoprotective agents include amifostine (ETHYOL®),glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD®or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known ascalcium leucovorin, citrovorum factor and folinic acid).

In yet another aspect, a compound of the present invention may be usedin combination with known therapeutic processes, for example, with theadministration of hormones or in radiation therapy. In certaininstances, a compound of the present invention may be used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

In yet another aspect, the present invention provides kits comprisingone or more compounds of the present invention and another therapeuticagent as described above. Representative kits include (a) compound ofFormula (I) or sub-formulae thereof or a pharmaceutically acceptablesalt thereof; and (b) at least one other therapeutic agent e.g., asindicated above; whereby such kit may further comprise a package insertor other labeling including directions for administration. The kits ofthe invention may be used for administering different dosage forms, forexample, oral and parenteral; for administering two or more separatepharmaceutical compositions at different dosage intervals; or fortitrating the separate compositions against one another; wherein atleast one pharmaceutical composition comprises a compound a Formula (I)or sub-formulae thereof.

EXAMPLES

Temperatures are given in degrees Celsius. The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Unless otherwise specified, startingmaterials are generally available from commercial sources.

The Examples herein merely illuminate the invention and does not limitthe scope of the invention otherwise claimed. Further, the compounds ofthe present invention can be produced by organic synthesis methods knownto one of ordinary skill in the art as shown in the following examples.Where desired, conventional protecting groups are used to protectreactive functional groups in accordance with standard practice, forexample, see T.W. Greene and P.G.M. Wuts in “Protecting Groups inOrganic Synthesis”, John Wiley and Sons, 1991.

Abbreviations

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “aq” foraqueous, “FCC” for flash column chromatography, “eq” for equivalent orequivalents, “g” for gram or grams, “mg” for milligram or milligrams,“L” for liter or liters, “mL” for milliliter or milliliters, “μL” formicroliter or microliters, “N” for normal, “M” for molar, “nM” fornanomolar, “mol” for mole or moles, “mmol” for millimole or millimoles,“min” for minute or minutes, “h” or “hrs” for hour or hours, “RT” forroom temperature, “ON” for overnight, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “sat” or “sat'd” forsaturated, “MW” for molecular weight, “mw” or “pwave” for microwave,“mp” for melting point, “Wt” for weight, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” or “LC-MS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tIc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “b” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, “ee” for “enantiomeric excess” and “α”, “β”, “R”,“r”, “S”, “s”, “E”, and “Z” are stereochemical designations familiar toone skilled in the art.

The following abbreviations used herein below have the correspondingmeanings:

Δ heat AIBN azobisisobutyronitrile AcOH acetic acid Bn Benzyl Boctert-butyloxycarbonyl Boc₂O di-tert butyl dicarbonate B(OMe)₃ trimethylborate BSA bovine serum albumin Cbz benzyloxycarbonyl CbzCl benzylchloroformate CDCl₃ chloroform-d CD₃OD methanol-d₄ dd doublet ofdoublets DAST diethylaminosulfur trifluoride DCM dichloromethane DEADDiethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIPEAN,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMEM DulbeccoModified Eagle Medium DMF dimethylformamide DMP Dess-Martin periodinaneDMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EA ethyl alcoholEtOAc ethyl acetate EtOH ethanol FBS fetal bovine serum HATUHexafluorophosphate Azabenzotriazole Tetramethyl Uronium) KHMDSpotassium bis(trimethylsilyl)amide LiHMDS lithiumbis(trimethylsilyl)amide MeOH methanol MgSO₄ magnesium sulfate MHzmegahertz min minutes m/z mass to charge ratio NaHCO₃ sodium bicarbonateNa₂SO₄ sodium sulfate NBS N-bromosuccinimide NH₄Cl ammonium chloridePBu₃ tributylphosphine Pd(dppf)Cl₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) PEpetroleum ether Phl(OAc)₂ (diacetoxyiodo)benzene ppm parts per millionrac racemic SFC Supercritical fluid chromatography TBAFtetra-n-butylammonium fluoride TEA triethylamine TFA trifluoroaceticacid THF tetrahydrofuran TMSI trimethylsilyl iodide UV ultraviolet

High performance liquid chromatography (HPLC) was performed using anAgilent 1260 HPLC System (Santa Clara, Calif.). The analytical columnwas reversed phase Phenomenex Kinetex C18-2.6 μm, 4.6×50 mm. A gradientelution was used (flow rate 2.0 mL/min), starting with 5% methanol/95%water and progressing to 95% methanol/5% water over a period of 10minutes. All solvents contained 0.1% formic acid (FA). Compounds weredetected by ultraviolet light (UV) absorption at 214, 254 and 300 nm.HPLC solvents were purchased from Sigma Aldrich (St. Louis, Mo.).

Mass spectrometric analysis was performed on an Agilent System (Agilent1260 HPLC and an Agilent 6130 mass spectrometer detector; Column:Phenomenex Kinetex 2.6 um C18, column size 4.6×50 mm; column temperature40° C.; gradient: 5 95% methanol in water with 0.1% FA over a 2 minperiod; flow rate 2.0 mL/min (or Polar gradient 5-50% over 2.0 min, orNon-Polar gradient 50-95% over 2.0 min); Mass Spectrometer molecularweight scan range 100 1000; or 100-1500; capillary voltage 4000 V. Allmasses were reported as those of the protonated parent ions, unlessotherwise indicated.

Nuclear magnetic resonance (NMR) analysis was performed using a Bruker400 MHz NMR. The spectral reference was either TMS or the known chemicalshift of the solvent.

Chiral Preparative HPLC Methods Employed in Purification of Examples

SFC chiral screening was carried out on a Thar Insturments Investigatorsystem. The Thar Investigator system consists of:

-   -   ALIAS autosampler    -   Thar Fluid Delivery Module (0 to 10 mL/min)    -   Thar SFC 10 position column oven    -   Waters 2998 PDA    -   Thar Automated Back Pressure Regulator

All of the Thar components are part of the SuperPure Discovery Seriesline. The system flowed at 3.0 mL/min and kept at 38° C. The system backpressure was set to 100 bar. Each sample was screened through a batteryof ten 5 μm columns:

-   -   5 μm 4.6×150 mm ChiralPak AD    -   5 μm 4.6×150 mm ChiralCel OD    -   5 μm 4.6×150 mm ChiralCel OJ    -   5 μm 4.6×150 mm ChiralPak AS    -   5 μm 4.6×250 mm ChiralPak AY    -   5 μm 4.6×250 mm ChiralCel OZ    -   5 μm 4.6×150 mm ChiralPak IC    -   5 μm 4.6×150 mm ChiralPak IG    -   5 μm 4.6×250 mm Regis Whelk-01    -   5 μm 4.6×250 mm ChromegaChiral CC4

The system ran a gradient from 5% co-solvent to 50% co-solvent in 9minutes followed by a 10 minutes hold at 50% co-solvent, a switch backto 5% co-solvent and a 0.5 minute hold at initial condition. In betweeneach gradient there was a 4 minute equilibration method that flows 5%co-solvent through the next column to be screened. The typical solventsscreened were, MeOH, EtOH, IPA, MeOH+0.5% NH₃, EtOH+0.5% NH₃, IPA+0.1%NH₃. Once separation was detected using one of the gradient methods, anisocratic method can be developed, and if necessary, scaled up forseparation on the Thar Prep 80 system.

INTERMEDIATES Intermediate A: Methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate

A mixture of compound methyl 2-bromo-5-fluoroisonicotinate (110 g,470.04 mmol, 1.0 eq.), (3,4-difluorophenyl)boronic acid (111.34 g,705.06 mmol, 1.5 eq), Pd(dppf)Cl₂ (8.60 g, 11.75 mmol, 0.025 eq) andpotassium carbonate (129.92 g, 940.08 mmol, 2.0 eq) in 1,4-dioxane (1.Pd(dppf)Cl₂ 1 L) was heated to 100° C. for 16 hours under N₂. Themixture was diluted with H₂O (500 mL) and EtOAc (1.3 L) and stirred for15 mins. The organic layer was separated, washed with brine (500 mL),dried over Na₂SO₄ and concentrated, the residue purified by combi-flash(5%-50% EtOAcin PE) and trituration (PE:EA=50/1, 100 mL) to affordmethyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate (Intermediate A). ¹HNMR (CDCl₃ 400 MHz): δ 8.56 (d, J=2.0 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H),7.79 (ddd, J=2.4, 8.4, 10.8 Hz, 1H), 7.64 (td, J=2.8, 8.8 Hz, 1H),7.26-7.11 (m, 1H), 3.94 (s, 3H).

To a solution of compound 9H-purin-6-amine (15 g, 111 mmol) in THF (500mL) were added di-tert butyl dicarbonate (Boc₂O) (96.91 g, 444 mmol) andDMAP (1.36 g, 11.1 mmol). The resulting mixture was stirred at RT for 16h. The THF was removed in vacuo. The residue was partitioned betweenEtOAc (400 mL) and HCl solution (1.0 M in H₂O) (200 mL). The organiclayer was dried over Na₂SO₄ and concentrated to give tert-butyl6-(bis(tert-butoxycarbonyl)amino)-9H-purine-9-carboxylate (IntermediateB-1).

To a solution of tert-butyl6-(bis(tert-butoxycarbonyl)amino)-9H-purine-9-carboxylate (IntermediateB-1) (48 g, 110 mmol) in MeOH (500 mL) was added sat.NaHCO₃ solution(250 mL). The resulting mixture was heated at 60° C. for 2 h. The MeOHwas removed in vacuo. The residue was extracted with a solution ofMeOH:DCM (1:10) (300 mL*7 times). The combined organic layers werewashed with H₂O (150 mL), dried over Na₂SO₄ and concentrated. Theresidue was washed with a solution of EtOAc:PE (1:10) (100 mL) andfiltered. The filter cake was dried in vacuo to get give Intermediate B.¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.48 (s, 1H), 1.36 (s, 18H).LC-MS: [M+H)]⁺=336.2.

Intermediate C: Methyl 5-fluoro-2-(3-fluorophenyl)isonicotinate

Methyl 5-fluoro-2-(3-fluorophenyl)isonicotinate (Intermediate C) wasprepared by using a procedure similar to that of Intermediate A. ¹H-NMR(400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.18 (d, J=6.4 Hz, 1H), 7.76-7.72 (m,2H), 7.48-7.42 (m, 1H), 7.15-7.11 (m, 1H), 4.01 (s, 3H).

Intermediate D: Methyl5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinate

A suspension of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol),(3-fluoro-4-methoxyphenyl)boronic acid (1.089 g, 6.41 mmol), Cs₂CO₃(2.78 g, 8.55 mmol) and PdCl₂(dppf) CH₂Cl₂ adduct (0.349 g, 0.427 mmol)in dioxane (10 mL) was stirred at 100° C. under Ar for 2 hr. Then themixture was diluted with water, extracted with EtOAc, the organic layerwas dired over Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by CombinFlash (PE/EA, EA: 20-40% for 50 mins) to affordmethyl 5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinate (IntermediateD). ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (t, 1H), 8.24 (t, 1H), 7.95-7.87(m, 2H), 7.27 (t, 3H), 3.92 (d, 6H). LC-MS: [M+H]⁺=279.9.

Intermediate F-2:2-(2-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 2-bromo-5-fluorobenzaldehyde (8 g, 39.4 mmol) in DCM(30 mL), was added DAST (10.41 mL, 79 mmol) at 0° C., then the mixturewas stirred at rt for 18 hr under N₂. The reaction mixture was washedwith water, the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by Combinflash (elutiongradient: 0% to 10% EtOAc in n-hexane in 30 mins) to afford1-bromo-2-(difluoromethyl)-4-fluorobenzene (Intermediate F-1). LC-MS:[M+H]⁺=225.0, 227.0.

A suspension of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (IntermediateF-1) (2.2 g, 9.78 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (2.98 g,11.73 mmol) and KOAc (1.919 g, 19.56 mmol) and PdCl₂(dppf).CH₂Cl₂ (0.798g, 0.978 mmol) adduct in dioxane (30 mL) was stirred at 110° C. for 3 hrunder N₂ atmosphere. The mixture was diluted with water, extracted withEtOAc, the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by CombinFlash (elutiongradient: 0% to 10% EtOAc in PE in 30 mins) to afford2-(2-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate F-2) as a colorless syrup. LC-MS: [M+H]⁺=272.3.

Intermediate L-2:2-(2-(difluoromethyl)-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-bromo-2-(difluoromethyl)-4,5-difluorobenzene (Intermediate L-1) and2-(2-(difluoromethyl)-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate L-2) were prepared following procedures analogous to thepreparation of Intermediates F-1 and F-2, respectively.

Intermediate L-1: ¹H NMR (CDCl₃, 400 MHz): δ 7.54-7.45 (m, 2H),6.97-6.70 (t, J₁=54.8 Hz, J2=109.6 Hz, 1H).

Intermediate L-2: ¹H NMR (CDCl₃, 400 MHz): δ 7.75-7.66 (m, 1H),7.57-7.50 (m, 1H), 7.47-7.14 (m, 1H), 1.36 (s, 12H).

Intermediate O-1: 6-Bromo-2-chloro-3-fluoropyridine

To a solution of 6-bromo-2-chloro-3-fluoropyridine (3.0 g, 0.014 mol,1.0 eq.) and i-Pr₃O₃B (4.0 g, 0.021 mol, 1.5 eq.) in anhydrous THF (30mL) was added n-BuLi (9 mL, 0.021 mol, 2.5M sol., 1.5 eq.) dropwise at−78° C. The resulting mixture was stirred at −78° C. for 1 hour andwarmed to 20° C. for another 1 hour. The reaction was quenched withsaturated NH₄Cl (50 mL), acidified with conc. HCl topPH=4, stirred for 1hour at 20° C. Extracted with ethyl acetate (50 mL*3). The combinedorganic layer was dried over Na₂SO₄, concentrated in vacuo to afford6-bromo-2-chloro-3-fluoropyridine (Intermediate O-1). LC-MS:[M+H]⁺=176.0.

Intermediates E-O were prepared following procedures analogous to thepreparation of Intermediate A, from the reaction of methyl2-bromo-5-fluoroisonicotinate and corresponding boronic acid or ester.

LC-MS and/or Intermediate Boronic acid/ester ¹H NMR E

¹H NMR (400 MHz, CDCl₃) δ ppm 8.70 (s, 1H), 8.31- 8.29 (d, J = 5.6 Hz,1H), 7.79-7.90 (m, 1H), 7.11- 7.02 (m, 1H), 4.03 (s, 3H). LC-MS: [M +H]⁺ = 286.1. F

LC-MS: [M + H]⁺ = 300.1 G

LC-MS: [M + H]⁺ = 298.1.1 H

LC-MS: [M + H]⁺ = 312.1 I

LC-MS: [M + H]⁺ = 298.1 J

LC-MS: [M + H]⁺ = 330.1 K

LC-MS: [M + H]⁺ = 296.1 L

¹H NMR (CDCl₃, 400 MHz): δ 8.69-8.68 (d, J = 1.6 Hz, 1H), 7.97-7.95 (d,J = 6.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.47-7.37 (m, 1H), 7.21- 7.97 (m,1H), 4.02 (s, 3H), LC-MS: [M + H]⁺ = 318.2. M

LC-MS: [M + H]⁺ = 286.2 N

¹H NMR,(400 MHz, DMSO-d₆) δ 8.84 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 5.9Hz, 1H), 7.80 (dd, J = 8.7, 7.1 Hz, 1H), 7.12 (dd, J = 11.5, 2.5 Hz,1H), 6.93 (td, J = 8.4, 2.5 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H), LC-MS:[M + H]⁺ = 280.0. O

¹H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 5.9 Hz, 1H), 8.61 (d, J = 1.8Hz, 1H), 8.34 (dd, J = 3.5, 8.4 Hz, 1H), 7.63- 7.57 (m, 1H), 4.03 (s,3H). LC-MS: [M + H]⁺ = 285.1

Intermediate 1-1:5-Fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinaldehyde

A suspension of 2-bromo-5-fluoroisonicotinaldehyde (8 g, 27.5 mmol),(3-fluoro-4-methoxyphenyl) boronic acid (4.67 g, 27.5 mmol), PdCl₂(dppD).CH₂Cl₂ adduct (1.121 g, 1.373 mmol) and cesium carbonate (13.42g, 41.2 mmol) in dioxane (50 mL) was stirred at 10000 for 3 hr undernitrogen atmosphere. The reaction mixture was filtered and the filtratewas concentrated in vacuum to afford a black residue. The residue wasredissolved in DCM (60 mL), washed with water (20 mL), brine (20 mL),dried over anhydrous magnisium sulfate, filtered and concentrated invacuum. The residue was purified by silica gel column chromatography(EtOAc in hexane and DCM, EtOAc/DCM/Hexane=8/20/100) to give5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinaldehyde (Intermediate1-1). ¹H NMR (400 MHz, CDCl₃) δ 10.51 (d, J=2.1 Hz, 1H), 8.77 (d, J=1.9Hz, 1H), 8.07 (dd, J=5.3, 2.1 Hz, 1H), 7.85 (dd, J=12.5, 2.4 Hz, 1H),7.78 (d, J=8.6 Hz, 1H), 7.11 (td, J=8.6, 2.2 Hz, 1H), 4.01 (d, J=2.2 Hz,3H). LC-MS: [M+H]⁺=249.9.

Intermediate 22-7: tert-Butyl(3-(cyclopropoxymethyl)piperidin-3-yl)carbamate

To a solution of 1-(tert-butyl) 3-ethyl piperidine-1,3-dicarboxylate(70.0 g, 272 mmol, 1.0 eq.) in THF (1.4 L) was added dropwise LiHMDS(435 mL, 435 mmol, 1.6 eq., 1 M in THF) at −70° C. under N₂ atmosphere.After stirred at −78° C. for 1 hr, ((chloromethoxy)methyl)benzene (56.0g, 354 mmol, 1.3 eq.) was added at −78° C. The resulting mixture wasallowed to warm to 15-20° C. and stirred for 16 hr. The reaction wasquenched with water (800 mL), and extracted with EtOAc (800 mL×3). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by Combi Flash (10% EtOAc in PE) togive 1-(tert-butyl) 3-ethyl3-((benzyloxy)methyl)piperidine-1,3-dicarboxylate (22-1). ¹H NMR (400MHz, CDCl₃) δ ppm 7.20-7.40 (5H, m), 4.50 (2H, q, J=12.8 Hz), 4.10-4.20(2H, m), 3.65-3.85 (2H, m), 3.45-3.60 (2H, m), 3.30-3.45 (2H, m),1.90-2.10 (1H, m), 1.65-1.75 (1H, m), 1.50-1.60 (2H, m), 1.45 (9H, s),1.20-1.30 (3H, m). LC-MS: [M+H−100]⁺=278.1.

A mixture of 1-(tert-butyl) 3-ethyl3-((benzyloxy)methyl)piperidine-1,3-dicarboxylate (22-1) (50.0 g, 132mmol, 1.0 eq.) and Pd/C (5.00 g, 10% wet) in dioxane/2N HCl (1 L,v/v=1/1) was stirred under H₂ balloon at 20° C. for 16 hr. Then themixture was filtered and the filtrate was concentrated in vacuo. The pHof the residue was adjusted to 8-9 with NaHCO₃ aqueous.

Then THF (500 mL) and CbzCl (45.0 g, 265 mmol, 2.0 eq.) were added. Theresulting mixture was stirred at 5-10° C. for 24 hr. The mixture wasextracted with EtOAc (500 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by Combi Flash (30% EtOAc in PE) to give 1-benzyl 3-ethyl3-(hydroxymethyl)piperidine-1,3-dicarboxylate (22-2). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.30-7.40 (5H, m), 5.05-5.20 (2H, s), 4.05-4.20 (2H, m),2.60-4.05 (7H, m), 1.55-1.95 (4H, m), 1.15-1.30 (3H, m).

To a solution of 1-benzyl 3-ethyl3-(hydroxymethyl)piperidine-1,3-dicarboxylate (22-2) (31.0 g, 96.5 mmol,1.0 eq.) and Py (15.3 g, 193 mmol, 2.0 eq.) in DCM (300 mL) was addeddropwise Tf₂O (57.0 g, 193 mmol, 2.0 eq.) at −70° C. under N₂. Then themixture was allowed to warm to 10-15° C., and stirred for 1 hr. Thereaction was quenched with water (500 mL), and extracted with DCM (500mL×2). The combined organic layer was washed with water (500 mL×3),dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by Combi Flash (10% EtOAc in PE) to give 1-benzyl 3-ethyl3-((((trifluoromethyl)sulfonyl)oxy) methyl)piperidine-1,3-dicarboxylate(22-3). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.30-7.45 (5H, m), 5.05-5.25 (2H,s), 4.45-4.75 (2H, m), 4.05-4.25 (2H, m), 3.60-3.85 (2H, m), 3.20-3.40(3H, m), 1.95-2.10 (1H, m), 1.75-1.90 (1H, m), 1.60-1.75 (2H, m),1.15-1.30 (3H, m).

To a solution of compound cyclopropanol (3.20 g, 55.1 mmol, 1.0 eq.) inTHF (100 mL) was added NaH (60% in mineral oil, 2.70 g, 66.1 mmol, 1.2eq.) at 0° C. After stirred at 10-15° C. for 30 min, a solution of1-benzyl 3-ethyl3-((((trifluoromethyl)sulfonyl)oxy)methyl)piperidine-1,3-dicarboxylate(22-3) (27.0 g, 60.6 mmol, 1.1 eq) in THF (100 mL) was added at 0° C.The resulting mixture was stirred at 10-15° C. for 3 hr. The reactionwas quenched with water (500 mL), and extracted with EtOAc (500 mL×2).The combined organic layers were washed with water (500 mL×3), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by Combi Flash (20% EtOAc in PE) to 1-benzyl 3-ethyl3-(cyclopropoxymethyl) piperidine-1,3-dicarboxylate (22-4). ¹H NMR (400MHz, CDCl₃) δ ppm 7.25-7.45 (5H, m), 5.05-5.25 (2H, s), 4.05-4.20 (2H,m), 3.86 (1H, d, J=13.2 Hz), 3.30-3.60 (5H, m), 3.10-3.25 (1H, m),1.90-2.05 (1H, m), 1.50-1.70 (3H, m), 1.95 (3H, t, J=6.8 Hz), 0.30-0.55(4H, m).

A mixture of 1-benzyl 3-ethyl3-(cyclopropoxymethyl)piperidine-1,3-dicarboxylate (22-4) (10.0 g, 27.6mmol, 1.0 eq.) and LiOH.H₂O (11.6 g, 276 mmol, 10.0 eq.) in MeOH/THF/H₂O(120 mL, v/v/v=1/1/1) was stirred at 20° C. for 16 hr. Then the mixturewas concentrated in vacuo to remove THF and MeOH. The residue wasdiluted with water (300 mL), and extracted with EtOAc (200 mL). The pHof the aqueous layer was adjusted to 5 by 1N HCl, then the aqueous layerwas extracted with EtOAc (300 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo to give1-((benzyloxy)carbonyl)-3-(cyclopropoxymethyl)piperidine-3-carboxylicacid (22-5). ¹H NMR (400 MHz, CDCl₃) b ppm 7.25-7.45 (5H, m), 5.14 (2H,s), 3.79 (1H, d, J=13.6 Hz), 3.15-3.65 (6H, m), 1.90-2.00 (1H, m),1.50-1.80 (3H, m), 0.30-0.60 (4H, m).

A solution of1-((benzyloxy)carbonyl)-3-(cyclopropoxymethyl)piperidine-3-carboxylicacid (22-5) (6.00 g, 18 mmol, 1.0 eq), DPPA (5.50 g, 19.8 mmol, 1.1 eq)and Et₃N (3.60 g, 36 mmol, 2.0 eq.) in toluene (100 mL) was stirred at80° C. under N₂ for 2 hr. Then the reaction was concentrated in vacuo.The residue was dissolved in THF (100 mL). Then KOH (3.03 g, 54 mmol,3.0 eq) and water (10 mL) were added. The mixture was stirred at 15-20°C. for 4 hr. Then Boc₂O (5.90 g, 27 mmol, 1.5 eq) and K₂CO₃ (10.0 g, 72mmol, 4.0 eq) were added. The resulting mixture was stirred at 15-20° C.for 16 hr. The mixture was extracted with EtOAc (200 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by Combi Flash (15% EtOAc in PE) to givebenzyl3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidine-1-carboxylate(22-6). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.25-7.45 (5H, m), 5.05-5.25 (2H,m), 4.40-4.80 (1H, brs), 3.50-4.05 (4H, m), 3.00-3.35 (3H, m), 2.15-2.55(1H, m), 1.60-1.75 (1H, m), 1.35-1.55 (11H, m), 0.30-0.60 (4H, m).

A mixture of benzyl3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidine-1-carboxylate(22-6) (4.90 g, 12.1 mmol) and Pd/C (500 mg, 10% wet) in MeOH (100 mL)was stirred under H₂ balloon at 15-20° C. for 1 hr. Then the Pd/C wasfiltered off and the filtrate was concentrated in vacuo to givetert-butyl (3-(cyclopropoxymethyl)piperidin-3-yl)carbamate (Intermediate22-7). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.82 (1H, brs), 3.80 (1H, d, J=10.0Hz), 3.53 (1H, d, J=9.6 Hz), 3.20-3.30 (1H, m), 3.01 (1H, d, J=12.4 Hz),2.85-2.95 (1H, m), 2.55-2.65 (2H, m), 2.05-2.20 (1H, brs), 1.30-1.70(13H, m), 0.35-0.60 (4H, m).

Intermediate 47-6: tert-Butyl(3-(2,2-difluoroethyl)piperidin-3-yl)carbamate

To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (5 g,18.03 mmol) in THF (70 mL) was added 1M LHMDS in THF (19.83 mL, 19.83mmol) dropwise at −78° C. in 30 min. The mixture was stirred at −78° C.for another 30 min. Then 1,1-difluoro-2-iodoethane (6.92 g, 36.1 mmol)was added. The mixture was stirred at −78° C. for another 2 hr. Then thetemperature was allowed to increase to RT slowly, and the mixture wasallowed to stir at RT for overnight. The reaction was quenched byaddition of water (10 mL). The most THF was removed under reducedpressure. The residue was extracted with ethyl acetate (30 mL*2), thecombined organic phase washed with water (20 mL), brine (20 mL), diredover anhydrous magnisium sulfate, filtered and concentrated. The crudeproduct was purified by flash chromatography (elution gradient: 5% to20% EtOAc in hexane in 40 mins) to afford 1-benzyl 3-methyl3-(2,2-difluoroethyl)piperidine-1,3-dicarboxylate (47-1). LC-MS:[M+H]⁺=341.9.

To a solution of 1-benzyl 3-methyl3-(2,2-difluoroethyl)piperidine-1,3-dicarboxylate (47-1) (6 g, 17.58mmol) in methanol (50 mL) was added lithium hydroxide (4.21 g, 176 mmol)in water (30 mL). The mixture was stirred at RT overnight and thesolvent was removed. The residue was diluted with water (20 mL), thenthe mixture was washed with ethyl acetate (5 mL), and the aqueous layerwas acidified by HCl to PH=3. Then the mixture was extracted with DCM(20 mL*3). The combined organic layer was dried over anhydrous magnisiumsulfate, filtered and concentrated in vacuo to afford crude1-((benzyloxy)carbonyl)-3-(2,2-difluoroethyl)piperidine-3-carboxylicacid (47-2). LC-MS: [M+H]⁺=328.1.

To a solution of1-((benzyloxy)carbonyl)-3-(2,2-difluoroethyl)piperidine-3-carboxylicacid (47-2) (5 g, 15.28 mmol) in Toluene (70 mL) was added TEA (4.26 mL,30.6 mmol) and DPPA (3.70 mL, 16.80 mmol). The mixture was stirred at100° C. under nitrogen protection for 2 hr. The mixture was diluted withethyl acetate (60 mL), washed with water (20 mL), brine (60 mL). Theorganic phase was dried over anhydrous magnisium sulfate, filtered andconcentrated to give crude benzyl3-(2,2-difluoroethyl)-3-isocyanatopiperidine-1-carboxylate (47-3).LC-MS: [M+H]⁺=325.1.

To a solution of benzyl3-(2,2-difluoroethyl)-3-isocyanatopiperidine-1-carboxylate (47-3) (5.7g, 12.30 mmol) in 1,4-dioxane (25 mL) was added 6M HCl (25 mL, 150mmol). The mixture was stirred at 45° C. for 30 hr. The mixture wascooled to rt and diluted with 20 ml of water. Then it was washed withethyl acetate (5 mL). The aqueous phase was basified with sodiumhydroxide to adjust the pH value to 9. Then the mixture was extractedwith DCM (30 mL*3). The organic layer was combined and dried overanhydrous magnisium sulfate, filtered and concentrated to afford crudebenzyl 3-amino-3-(2,2-difluoroethyl)piperidine-1-carboxylate (47-4).LC-MS: [M+H]+=299.2.

To a solution of benzyl3-amino-3-(2,2-difluoroethyl)piperidine-1-carboxylate (intermediate47-4) (4 g, 13.41 mmol) in DCM (50 mL) was added Boc-anhydride (4.67 mL,20.11 mmol) and DIPEA (7.03 mL, 40.2 mmol) at RT under N₂ atmosphere.The mixture was stirred at 40° C. for 20 h. The mixture was cooled to RTand diluted with DCM (30 mL), washed with water (20 mL), brine (20 mL),dried over anhydrous magnisium sulfate, filtered and concentrated invacuo to afford the crude product. The crude product was purified byflash chromatography (elution gradient: 5% to 20% EtOAc in hexane in 30mins) to afford benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidine-1-carboxylate(47-5). LC-MS: [M+H]⁺=399.0.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidine-1-carboxylate(47-5) (4 g, 10.04 mmol) in methanol (50 mL) was added 10% Pd(OH)₂ oncarbon, wet (1.410 g, 0.502 mmol), the mixture was stirred at rt for 3hr under a hydrogen balloon. The reaction mixture was filtered andconcentrated to afford the crude tert-butyl(3-(2,2-difluoroethyl)piperidin-3-yl)carbamate (Intermediate 47-6).LC-MS: [M+H]⁺=265.0.

Intermediate 78-5: Methyl tert-butyl3-(methylcarbamoyl)piperidin-3-ylcarbamate

To a solution of (NH₄)₂CO₃ (2.13 g, 22 mmol) in H₂O (8 mL) was addedanother solution of 1-benzylpiperidin-3-one (500 mg, 2 mmol) in EtOH (8mL). Then trimethylsilyl cyanide (TMSCN) (0.74 mL, 5.5 mmol) was addedto the mixture dropwise at RT. The resulting mixture was stirred at 70°C. for 16 h. The EtOH was removed in vacuo. The resulting mixture wasextracted with EtOAc (20 mL*3). The organic layer was washed with H₂O(20 mL), brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue obtained was recrystallized from EtOAc:PE (1: 5) to give7-benzyl-1,3,7-triazaspiro[4.5]decane-2,4-dione (78-1). ¹H NMR (400 MHz,CD₃OD) δ 7.46-7.17 (m, 5H), 3.54 (dd, J=29.8, 13.2 Hz, 2H), 2.90 (d,J=10.8 Hz, 1H), 2.69 (d, J=11.2 Hz, 1H), 2.32 (d, J=11.2 Hz, 1H), 2.08(t, J=10.6 Hz, 1H), 1.88-1.59 (m, 4H). LC-MS (UV 214): (M+H)⁺=260.1

A mixture of 7-benzyl-1,3,7-triazaspiro[4.5]decane-2,4-dione (78-1) (1g, 3.86 mmol) in 10 M of 2.0 M KOH aqueous solution was heated at 120°C. for 16 h. The mixture was cooled to RT. Con. HCl solution (12.0 M inH₂O) was added to the mixture to adjust pH=4-5. The H₂O was removed invacuo. The residue was washed with a solution of MeOH:DCM (10%, 30 mL)and filtered. The filtrate was dried over Na₂SO₄ and concentrated togive crude 3-amino-1-benzylpiperidine-3-carboxylic acid (78-2). LC-MS[M+H]⁺=235.3.

A mixture of 3-amino-1-benzylpiperidine-3-carboxylic acid (78-2) (5.7 g,24.33 mmol), K₂CO₃ (13.45 g, 97.31 mmol), Boc₂O (8.2 mL, 36.49 mmol),THF (100 mL) and H₂O (100 mL) was stirred at RT for 16 h. The reactionmixture was extracted with EtOAc, the combined organic phase was washedwith water, brine, dried over anhydrous sodium sulfate, concentrated togive a residue. The residue was purified by combi-flash (silica gel,KMnO₄, NH₃.H₂O:MeOH:DCM, 20:100:1000) to give1-benzyl-3-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid(78-3). LC-MS: [M+H]⁺=335.3.

To a solution of1-benzyl-3-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (78-3)(670 mg, 2.00 mmol), HATU (1.5 g, 4.00 mmol) and DIPEA (778 mg, 6.00mmol) in DCM (20 mL), was added CH₃NH₂ (35% in MeOH, 2 mL). The mixturewas stirred at RT for 1 h. The reaction mixture was diluted with water,extracted with EtOAc, the combined organic phase was washed with sat.aq. NaHCO₃ (20 mL), brine (20 mL), dried over anhydrous sodium sulfate,concentrated to give a residue. The residue was purified by flashchromatography (elution gradient: 10% to 50% EtOAc in PE in 30 mins) toafford tert-butyl 1-benzyl-3-(methylcarbamoyl)piperidin-3-ylcarbamate(78-4). LC-MS: [M+H]⁺=348.3.

To a solution of tert-butyl1-benzyl-3-(methylcarbamoyl)piperidin-3-ylcarbamate (78-4) (290 mg,0.836 mmol) in EtOH (10 mL) was added Pd(OH)₂ (87 mg). The resultingmixture was stirred at RT for 4 h under H₂ atmosphere. The mixture wasfiltered and the filtrate was concentrated to give crude methyltert-butyl 3-(methylcarbamoyl)piperidin-3-ylcarbamate (Intermediate78-5). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.29 (s, 1H), 3.62-3.59(m, 1H), 3.04-2.87 (m, 3H), 2.61-2.60 (m, 3H), 1.83-1.76 (m, 3H),1.53-1.51 (m, 1H), 1.38 (s, 9H), 1.27-1.25 (m, 1H). LC-MS (UV 214):[M+H]⁺=258.4.

Intermediate 89-6: Methyl(3-(2,3-dimethylbutanoyl)piperidin-3-yl)carbamate

To a solution of tert-butyl 3-cyanopiperidine-1-carboxylate (10 g, 47.6mmol, 1.0 eq.) in dry THF (100 mL) was added 1M LiHMDS (71.4 mL, 71.4mmol, 1.5 eq) dropwise at −78° C. under nitrogen. The mixture wasstirred at −78° C. for 40 min. Then 3-methylbutanal (6.1 g, 71.4 mmol,1.5 eq.) was added in one portion at −78° C. Then the mixture wasstirred at RT for 4 hours. The mixture was quenched with water (200 mL),extracted with EA (100 mL*2), washed with brine (200 mL), dried overanhydrous sodium sulfate, filtered, concentrated. The residue waspurified by flash chromatography (PE/EA=92/8 to 90/10 to 70/30) to givetert-butyl 3-cyano-3-(1-hydroxy-3-methylbutyl)piperidine-1-carboxylate(89-1). ¹H NMR (400 MHz, CD₃OD) δ ppm 4.57 (d, J=13.6 Hz, 0.5H),4.24-3.93 (m, 1.5H), 3.56 (dd, J=1.6, 10.8 Hz, 0.5H), 3.52-3.42 (m,0.5H), 3.09-2.56 (m, 2H), 2.22-2.09 (m, 0.5H), 2.01-1.82 (m, 1.5H),1.78-1.53 (m, 4H), 1.48 (s, 9H), 1.41-1.29 (m, 1H), 0.99 (dd, J=1.6, 6.8Hz, 3H), 0.95-0.89 (m, 3H). LC-MS: [M+H]⁺=297.2

To a solution of tert-butyl3-cyano-3-(1-hydroxy-3-methylbutyl)piperidine-1-carboxylate (89-1) (5.5g, 18.5 mmol, 1.0 eq.) in CH₂Cl₂ (100 mL) was added DMP (11.8 g, 27.8mmol, 1.5 eq.). The mixture was stirred at RT for 30 min. The mixturewas diluted with H₂O (100 mL) and extracted with CH₂Cl₂ (100 mL*2). Theorganic layers were washed with brine (200 mL), dried over sodiumsulfate, filtered, concentrated and purified by combi-flash(PE/EA=80/20) to afford tert-butyl3-cyano-3-(3-methylbutanoyl)piperidine-1-carboxylate (89-2). ¹H NMR (400MHz, CDCl₃) δ ppm 4.59-3.90 (m, 2H), 3.22-2.92 (m, 1H), 2.87-2.58 (m,3H), 2.29-2.03 (m, 2H), 1.98-1.69 (m, 3H), 1.50 (s, 9H), 1.03-0.89 (m,6H). LC-MS: [M+H]⁺=295.1.

To a solution of tert-butyl3-cyano-3-(3-methylbutanoyl)piperidine-1-carboxylate (89-2) (3.3 g, 11.2mmol, 1.0 eq.) in THF (40 mL) was added LiHMDS (12.3 mL, 12.3 mmol, 1.1eq. 1M in THF) dropwise at −78° C. under N₂. The mixture was stirred at−78° C. for 20 min. Then MeI (1.8 g, 12.3 mmol, 1.1 eq.) was added tothe mixture. The mixture was stirred at RT for another 4 hours. Thereaction was quenced with H₂O (40 mL) and extracted with EtOAc (40mL*2). The organic layers were combined and washed with brine (100 mL),dried over sodium sulfate, filtered, concentrated and purified bycombi-flash (5% EtOAc in hexane) to give tert-butyl3-cyano-3-(2,3-dimethylbutanoyl)piperidine-1-carboxylate (89-3). ¹H NMR(400 MHz, CD₃OD) δ ppm 4.50-4.02 (m, 2H), 3.23-2.64 (m, 3H), 2.27-1.72(m, 5H), 1.49 (s, 9H), 1.16-1.06 (m, 3H), 1.01-0.88 (m, 6H). LC-MS:[M+H]⁺=310.2.

To a mixture of tert-butyl3-cyano-3-(2,3-dimethylbutanoyl)piperidine-1-carboxylate (89-3) (3.3 g,11 mmol, 1.0 eq.) in MeOH (40 mL) was added NaOH (21 mL, 21 mmol, 1 M/L)and H₂O₂ (17 ml, 30% aq. solution). The mixture was stirred at RT for 16hours. The mixture was quenched with saturated aqueous Na₂SO₃ (100 mL),extracted with EtOAc (100 mL*2). The combined organic layers were washedwith brine (150 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (15%-30% EtOAc in PE) to give tert-butyl3-carbamoyl-3-(2,3-dimethylbutanoyl)piperidine-1-carboxylate (89-4). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.15 (brs, 1H), 5.35 (brs, 1H), 4.78-2.28 (m,5H), 1.94-1.57 (m, 5H), 1.47 (s, 9H), 1.00 (dd, J=7.2, 20.0 Hz, 3H),0.90-0.80 (m, 6H). LC-MS: [M+H]⁺=327.0.

To a solution of tert-butyl3-carbamoyl-3-(2,3-dimethylbutanoyl)piperidine-1-carboxylate (89-4)(1.37 g, 4.2 mmol, 1.0 eq.) in MeOH (30 mL) was added PhI(OAc)₂ (1.6 g,5.04 mmol, 1.2 eq.) and KOH (589 mg, 10.5 mmol, 2.5 eq.). The mixturewas stirred at 0° C. for 15 minutes. The mixture was stirred at RT foranother 2 hours. The mixture was diluted with H₂O (40 mL), extractedwith EtOAc (40 mL*2). The combined organic layers were washed with brine(40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography (20%EtOAc in PE) to give tert-butyl3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(89-5). ¹H NMR (400 MHz, CD₃OD): δ 4.74-4.42 (m, 1H), 4.14-3.91 (m, 1H),3.80-3.48 (m, 3H), 3.29-3.12 (m, 1H), 2.96-2.64 (m, 2H), 1.98-1.50 (m,5H), 1.43 (s, 9H), 1.01-0.85 (m, 9H). LC-MS: [M+H]⁺=357.1.

To a solution of tert-butyl3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(89-5) (500 mg, 1.40 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (10 mL)at RT. The mixture was stirred at RT for 30 minutes. The mixture wasconcentrated in vacuo and diluted with H₂O (15 mL), basified by NH₃H₂Oto pH=11, extracted with CHCl₃/i-PrOH (3:1, 20 mL*3). The combinedorganic layers were washed with brine (30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give methyl(3-(2,3-dimethylbutanoyl)piperidin-3-yl)carbamate (Intermediate 89-6).¹H NMR (400 MHz, CD₃OD) δ ppm 3.63 (s, 3H), 3.27-3.20 (m, 1H), 3.07-2.95(m, 1H), 2.92-2.81 (m, 2H), 2.66-2.55 (m, 1H), 2.10-2.00 (m, 1H),1.94-1.76 (m, 2H), 1.72-1.57 (m, 1H), 1.54-1.44 (m, 1H), 1.00-0.95 (m,3H), 0.91-0.74 (m, 6H). LC-MS: [M+H]⁺=257.1.

Intermediate 113-5: tert-Butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate

To a solution of 1-benzyl 3-ethyl3-((tert-butoxycarbonyl)amino)piperidine-1,3-dicarboxylate (5.0 g, 12.30mmol) in THF (80 mL) and methanol (80 mL), was added lithium chloride(10.43 g, 246 mmol) and sodium tetrahydroborate (9.31 g, 246 mmol) at rtunder N₂ atmosphere, the reaction mixture was stirred at RT for 18 hoursunder N₂ atmosphere. The reaction mixture was diluted with water,extracted with EtOAc (50 mL*3), the combined organic phase was washedwith water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate,concentrated to give a crude product. The crude product was purified byflash chromatography (elution gradient: 10% to 50% EtOAc in PE in 30mins) to give benzyl3-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)piperidine-1-carboxylate(113-1). LC-MS: [M+H]⁺=365.2.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-(hydroxymethyl)piperidine-1-carboxylate(113-1) (6.2 g, 17.01 mmol) in DCM (50 mL) was added Dess-MartinPeriodinane (14.43 g, 34.0 mmol) at 0° C. under N₂ atmosphere, thereaction mixture was stirred at RT for 2 h under N₂ atmosphere. Thereaction mixture was diluted with 30 ml of sat. NaHCO₃ aqueous solution,extracted with DCM (40 mL*3), the combined organic phase was washed withwater (50 mL), brine (50 mL), dried over anhydrous sodium sulfate,concentrated to give a crude product. The crude product was purified byflash chromatography (elution gradient: 10% to 40% EtOAc in PE in 30mins) to afford benzyl3-((tert-butoxycarbonyl)amino)-3-formylpiperidine-1-carboxylate (113-2).LC-MS: [M+H]⁺=362.1.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-formylpiperidine-1-carboxylate (113-2)(3 g, 8.28 mmol) and (difluoro(phenylsulfonyl)methyl)trimethylsilane(4.38 g, 16.56 mmol) in anhydrous THF (50 mL) was added a solution ofTBAT (0.447 g, 0.828 mmol) in 15 mL anhydrous THF dropwise at −78° C.under N₂ atmosphere. After addition, the reaction mixture was slowlywarmed to rt and stirred at rt for 18 h under N₂ atmosphere. And thenTBAF (10.76 mL, 10.76 mmol) was added and the reaction mixture wasstirred at rt for another 30 min. The reaction mixture was diluted sat.NaCl solution, extracted with EtOAc (50 mL*3), the combined organicphase was washed with water (40 mL), brine (40 mL), dried over anhydroussodium sulfate, and concentrated to give a crude product. The crudeproduct was purified by flash chromatography (elution gradient: 10% to50% EtOAc in hexane in 40 mins) to afford benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxy-2-(phenylsulfonyl)ethyl)piperidine-1-carboxylate (113-3). LC-MS: [M+H]⁺=555.2.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxy-2-(phenylsulfonyl)ethyl)piperidine-1-carboxylate (113-3) (2.4 g, 4.33 mmol) in DMF (50 mL), wasadded 40 mL of HOAc/NaOAc (1:1) buffer solution (4 mol/L). Magnesiumturning (1.578 g, 64.9 mmol) were added in portions. The reactionmixture was stirred at room temperature for 4 h. The reaction wasquenched with water and extracted with EtOAc (30 mL*3). The combinedorganic layers were washed with water (30 mL), brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash chromatography (elution gradient: 0% to40% EtOAc in PE in 40 mins) to afford benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidine-1-carboxylate(113-4). LC-MS: [M+H]⁺=415.2.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidine-1-carboxylate(113-4) (1.0 g, 2.413 mmol) in MeOH (50 mL) was added Pd(OH)₂ (0.068 g,0.483 mmol) at RT, the reaction mixture was stirred at RT for 0.5 hunder H₂ atmosphere. The reaction mixture was filtered and concentratedto give tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate (Intermediate113-5). LC-MS: [M+H]+=281.

Intermediate 156-2:1-(3-amino-1-(4-(hydroxymethyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

To a mixture of methyl 5-fluoro-2-(2,4,5-trifluorophenyl)isonicotinate(Intermediate E) (2.5 g, 8.77 mmol) and1-(3-aminopiperidin-3-yl)-2,2-difluoroethan-1-ol (Intermediate 113-5A)(3.58 g, 8.77 mmol) in DMSO (40 ml) was added DIPEA (40 ml, 229 mmol).The mixture was heated to 100° C. for 3 hrs. The mixture was cooled toroom temperature and was treated with EtOAc (50 ml) and H₂O (50 ml). Thelayers were separated and the aqueous layer was extracted with EtOAc (50ml*3). The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated. The residue waspurified, eluting with EtOAc in n-hexane (0 to 50%) to give methyl5-(3-amino-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)isonicotinate(Intermediate156-1). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.09-7.98 (m, 1H), 7.92(ddd, J=11.3, 9.1, 7.2 Hz, 1H), 7.04 (td, J=10.2, 6.4 Hz, 1H), 5.92 (td,J=55.2, 3.5 Hz, 1H), 3.98 (s, 3H), 3.65 (td, J=12.9, 3.5 Hz, 1H),3.36-3.21 (m, 2H), 3.11 (d, J=11.8 Hz, 1H), 2.99 (ddd, J=12.2, 10.2, 3.2Hz, 1H), 2.02 (tdd, J=15.2, 9.7, 4.6 Hz, 1H), 1.88-1.65 (m, 3H). LC-MS:[M+H]⁺=446.1.

To a mixture of methyl5-(3-amino-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)isonicotinate(Intermediate 156-1) (3.2 g, 7.18 mmol) and LiCl (6.09 g, 144 mmol) inMeOH (100 ml) and THF (100 ml) was added NaBH4 (5.44 g, 144 mmol) at 0°C. the mixture was stirred at room temperature for 4 hrs. LC-MSindicated most of sm was consumed. The mixture was quenched with H₂O (50ml) and was extracted with EtOAc (50 ml*4). The combined organic layerswere washed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated. The filtrate was concentrated and purified, eluting withMeOH in DCM (0 to 10%) to give1-(3-amino-1-(4-(hydroxymethyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Intermediate 156-2). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 7.89 (ddd,J=11.2, 9.1, 7.2 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.04 (td, J=10.2, 6.5Hz, 1H), 5.92 (td, J=55.2, 3.6 Hz, 1H), 5.12-4.62 (m, 2H), 3.68 (td,J=12.5, 3.6 Hz, 1H), 3.09 (dd, J=25.6, 10.6 Hz, 3H), 2.97-2.89 (m, 1H),2.09-1.72 (m, 4H). LC-MS: [M+H]⁺=418.2, 419.1.

Intermediate 158-3: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate (Intermediate113-5) (1.828 g, 4.48 mmol) and methyl2-(2-(difluoromethyl)-4-fluorophenyl)-5-fluoroisonicotinate(Intermediate F) (1.34 g, 4.48 mmol in DMSO (15 mL) was added DIPEA(15.64 mL, 90 mmol) at RT, the reaction mixture was stirred at 80° C.for 8 hr under N₂ atmosphere. The reaction mixture was diluted withwater (40 mL), extracted with EtOAc (30 mL*3). The combined organiclayers were washed with water (20 mL*3), brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue. Theresidue was purified by flash chromatography (elution gradient: 0% to10% MeOH in DCM in 40 mins) to afford methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)isonicotinate(Intermediate 158-1). LC-MS: [M+H]⁺=460.1.

To a solution of methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)isonicotinate(Intermediate 158-1) (1.5 g, 3.27 mmol) in THF (30 mL) and MeOH (30 mL),was added NaBH₄ (2.471 g, 65.3 mmol) and LiCl (2.77 g, 65.3 mmol). Thereaction mixture was stirred at 20° C. for 2 hr under N₂ atmosphere. Thereaction mixture was diluted with 30 ml of water, extracted with EtOAc(20 mL*3). The combined organic layers were washed with water (20 mL),brine (20 mL), concentrated to give a crude product. The crude productwas purified by flash chromatography (elution gradient: 0% to 10% MeOHDCM in 30 mins) to afford tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2-(difluoromethyl)-4-fluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 158-2). LC-MS: [M+H]⁺=432.

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2-(difluoromethyl)-4-fluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 158-2) (500 mg, 1.159 mmol), Intermediate B (389 mg, 1.159mmol) and PPh₃ (912 mg, 3.48 mmol) in THF (50 mL), was added DEAD (0.550mL, 3.48 mmol), the reaction mixture was stirred at 0° C. for 30 minunder N₂ atmosphere. The reaction mixture was diluted with 20 ml ofwater, extracted with EtOAc (20 mL*3). The combined organic layers werewashed with water (20 mL), brine (20 mL), concentrated to give a crudeproduct. The crude product was purified by flash chromatography (elutiongradient: 0% to 10% MeOH in DCM in 30 mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 158-3). LC-MS: [M+H]⁺=749.

Intermediate 160-3: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

To a solution of methyl2-(2,5-difluoro-4-methoxyphenyl)-5-fluoroisonicotinate (Intermediate G)(2.0 g, 6.73 mmol) and tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate (Intermediate113-5) (2.263 g, 8.07 mmol) in DMSO (10 mL) was added DIPEA (23.50 mL,135 mmol) under N₂ atmosphere, and the reaction mixture was stirred at120° C. for 6 hrs. The reaction mixture was diluted with water,extracted with EtOAc, the combined organic phase was washed with water,brine, dried over Na₂SO₄, concentrated to give a crude product. Thecrude product was purified by flash chromatography (elution gradient:10% to 50% EtOAc in n-hexane in 30 mins) to afford methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)isonicotinate(Intermediate 160-1). LC-MS: [M+H]+=558.1.

To a solution of methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4-fluorophenyl)isonicotinate(Intermediate 160-1) (1.9 g, 3.41 mmol) in THF (30 mL) and methanol (30mL) was added LiCl (0.068 g, 3.41 mmol) and NaBH₄ (0.068 g, 3.41 mmol)at 0° C. The reaction mixture was stirred at rt for 2 hours under N₂.The reaction mixture was diluted with water, extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over sodiumsulfate, concentrated to give a crude product. The crude product waspurified by flash chromatography (elution gradient: 10% to 60% EtOAc inn-hexane in 40 mins) to afford tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2,5-difluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate (Intermediate 160-2). LC-MS:[M+H]⁺=530.2.

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2,5-difluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 160-2) (1.2 g, 2.3 mmol), Intermediate B (0.76 g, 2.3mmol) and PPh₃ (1.783 g, 6.80 mmol) in THF (20 mL) was added DEAD (1.1mL, 6.8 mmol) dropwise at 0° C. under N₂ atmosphere, the reactionmixture was stirred at 0° C. for 0.5 hr under N₂ atmosphere. Thereaction mixture was quenched with water and extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over Na₂SO₄,concentrated to give a crude product. The crude product was purified byflash chromatography (elution gradient: 10% to 50% EtOAc in n-hexane in50 mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 160-3). LC-MS: [M+H]+=847.3.

The following intermediates were prepared following procedures analogousto the preparation of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2,5-difluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate (Intermediate 160-2), fromreacting the corresponding fluoroisonicotinate with1-(3-aminopiperidin-3-yl)-2,2-difluoroethan-1-ol (Intermediate 113-5A)(Intermediate Nos. 162-2, 164-2 and 166-2) or tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate (Intermediate113-5) (Intermediate Nos. 168-2, 170-2, 172-2).

Intermediate No. LC-MS 162-2

[M + H]+ = 444.2, 445.2 (Intermediate H) 164-2

[M + H]⁺ = 430.1 (Intermediate I) 166-2

[M + H]⁺ = 462.1 (Intermediate J) 168-2

[M + H]⁺ = 528.2 (Intermediate K) 170-2

[M + H]⁺ = 550.2 (Intermediate L) 172-2

[M + H]⁺ = 518.2 (Intermediate M) 174-2

[M + H]⁺ = 512.0 (Intermediate N) 175-2

[M + H]⁺ = 517.1 (Intermediate O)

Intermediate 168-3: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-chloro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

To a solution of tert-butyl(1-(6-(2-chloro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate(Intermediate 168-2) (0.5 g, 0.947 mmol, 1.0 eq), Intermediate B (0.318g, 0.947 mmol, 1.1 eq) and n-PPh₃ (0.745 g, 2.84 mmol, 3 eq) in THF (20mL), was added DIAD (0.552 mL, 2.84 mmol, 3 eq) dropwise at 0° C. underN₂ over 20 min, after addition the reaction mixture was stirred at RTfor 1 hr under N₂ atmosphere. The reaction mixture was diluted with 20ml of water, extracted with EtOAc (20 mL*3). The combined organic layerswere washed with water (20 mL), brine (20 mL), concentrated to give acrude product. The crude product was purified by flash chromatography(elution gradient: 20% to 70% EtOAc in n-hexane in 50 mins) to affordtert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-chloro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 168-3). LC-MS: [M+H]⁺=845.4.

Intermediate 170-4: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

Step 1. To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(2-(difluoromethyl)-4,5-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 170-2) (0.22 g, 0.40 mmol, 1.0 eq) in dry DCM (5 mL) wasadded dropwise thionyl chloride (0.146 mL, 2.02 mmol) at 0° C. Thereaction mixture diluted with sat. K₂CO₃ solution, extracted with DCM,washed with water (10 mL), brine (10 mL×2) and dried over Na₂SO₄,concentrated under reduced pressure to afford tert-butyl(1-(4-(chloromethyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate(Intermediate 170-3). LC-MS: [M+H]⁺=568.1.

Step 2. A suspension of tert-butyl(1-(4-(chloromethyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate(Intermediate 170-3) (0.24 g, 0.42 mmol, 1.0 eq), intermediate B (0.14g, 0.42 mmol) and K₂CO₃ (0.175 g, 1.27 mmol, 3.0 eq) in dry DMF (5 mL)was stirred at RT for 16 hours and quenched with water. The mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with water (10 mL*3), brine (10 mL) and dried over Na₂SO₄.filtered and concentration.

The crude product was purified by flash chromatography (elutiongradient: 10% to 70% EtOAc in m-hexane 50 mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 170-4). LC-MS: [M+H]⁺=867.3.

Intermediate 172-4: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,3,4-trifluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,3,4-trifluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 172-4) was obtained following analogous proceduresdescribed in Intermediate 170-4 from tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(4-(hydroxymethyl)-6-(2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 172-2). LC-MS: [M+H]⁺=835.2.

Intermediate 174-3: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(4-fluoro-2-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 174-2) (310 mg, 0.61 mmol), Intermediate B (203 mg, 0.61mmol) and PPh₃ (477 mg, 1.82 mmol) in THF (10 mL), was added DEAD (0.288mL, 1.82 mmol) dropwise at 0° C., after addition the reaction mixturewas stirred at RT for 0.5 hr under N₂ atmosphere. The reaction mixturewas diluted with 20 ml of water, extracted with EtOAc (20 mL*3). Thecombined organic layers were washed with water (20 mL), brine (20 mL),concentrated to give a crude product. The crude product was purified byflash chromatography (elution gradient: 10% to 70% EtOAc in PE in 50mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 174-3). LC-MS: [M+H]⁺=829.2.

Intermediate 175-3: tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-yl)carbamate

Tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 175-3) was obtained following procedures analogous toIntermediate 174-3. LC-MS: [M+H]⁺=834.1.

Intermediate 177-4: Methyl(3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamate hydrochlorideIntermediates 177-5: Methyl2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)isonicotinateIntermediate 177-6: Methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamateIntermediate 177-7: tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

To a solution of tert-butyl 3-cyanopiperidine-1-carboxylate (3.00 g,14.3 mmol, 1.0 eq.) and 2-fluoro-6-methylpyridine (1.66 g, 14.9 mmol,1.05 eq.) in THF (30 mL) was added dropwise KHMDS (17 mL, 17 mmol, 1.2eq., 1M in THF) at −70° C. under N₂ atmosphere. The resulting mixturewas allowed to warm to 25° C. and stirred for 12 hours. The reaction wasquenched with water (50 mL), and extracted with EtOAc (30 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by combi flash (20%EtOAc in PE) to give tert-butyl3-cyano-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate (177-1). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.64 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H),7.12 (d, J=8.0 Hz, 1H), 4.61-4.14 (m, 2H), 3.54-3.21 (m, 1H), 2.94-2.73(m, 1H), 2.55 (s, 3H), 2.40-2.24 (m, 1H), 2.23-2.12 (m, 1H), 2.06-1.92(m, 1H), 1.84-1.75 (m, 1H), 1.51 (s, 9H). LC-MS: [M+H]⁺=302.0.

To a solution of tert-butyl3-cyano-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate (177-1) (2.70g, 8.97 mmol, 1.0 eq.) in MeOH (30 mL) was added NaOH (10 mL, 1M) andH₂O₂ (5 mL, 30%). The reaction mixture was stirred at 25° C. for 12hours, quenched with sat.Na₂SO₃ (100 mL) and stirred at 25° C. for 1hour. The resulting mixture was concentrated in vacuo to remove MeOH.The aqueous was extracted with EtOAc (1000 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel (PE/EtOAc 5/1 to 1/1) togive tert-butyl3-carbamoyl-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate (177-2). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.54 (t, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz,1H), 7.03 (d, J=7.6 Hz, 1H), 5.48 (brs, 1H), 4.67-4.24 (m, 1H),3.91-3.43 (m, 2H), 3.21-2.95 (m, 1H), 2.72-2.55 (m, 1H), 2.53 (s, 3H),2.32-2.02 (m, 1H), 1.68-1.54 (m, 2H), 1.48 (s, 9H). LC-MS: [M+H]⁺=320.1.

To a solution of tert-butyl3-carbamoyl-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate (177-2)(2.40 g, 7.51 mmol, 1.0 eq.) and KOH (1.05 g, 18.8 mmol, 2.5 eq.) inMeOH (30 mL) was added PhI(OAc)₂ (2.42 g, 7.51 mmol, 1.0 eq.) at 0° C.The resulting mixture was stirred at 25° C. for 16 hours. The reactionwas concentrated in vacuo. The residue was purified by silica gel column(PE/EtOAc 10/1 to 3/1) to give tert-butyl3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate(177-3). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.55 (t, J=8.0 Hz, 1H), 7.26 (d,J=8.0 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 4.31-3.98 (m, 2H), 3.62 (s, 3H),3.14-2.82 (m, 1H), 2.53 (s, 3H), 2.48-2.09 (m, 1H), 1.82-1.67 (m, 2H),1.66-1.57 (m, 1H), 1.50 (s, 9H). LC-MS: [M+H]⁺=350.3.

To a mixture of tert-butyl3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate(177-3) (1.5 g, 4.30 mmol, 1.0 eq.) in DCM (10 mL) was added HCl/dioxane(10 mL, 4M), and the resulting mixture was stirred at 25° C. for 1 hour.The mixture was concentrated in vacuo to give methyl(3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamate hydrochloride(Intermediate 177-4). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.48-8.39 (m, 1H),7.92-7.78 (m, 2H), 4.33-4.25 (m, 1H), 4.09-4.01 (m, 1H), 3.68 (s, 3H),3.50-3.39 (m, 1H), 3.30-3.17 (m, 1H), 2.91 (s, 3H), 2.44-2.31 (m, 1H),2.30-2.14 (m, 2H), 2.06-1.94 (m, 1H). LC-MS: [M+H]⁺=250.0.

To a solution of methyl(3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamate hydrochloride(Intermediate 177-4) (1.22 g, 4.27 mmol, 1.0 eq.) in DMSO (10 mL) wasadded DIEA (3.86 g, 29.9 mmol, 7.0 eq.) and methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate (Intermediate A) (1.14 g,4.27 mmol, 1.0 eq.). The reaction mixture was stirred at 120° C. for 3hours. The reaction mixture was diluted with water (100 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EA 10/1 to 3/1) to give methyl2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)isonicotinate(177-5). H NMR (400 MHz, CDCl₃) δ ppm 8.52 (s, 1H), 7.94 (s, 1H),7.87-7.78 (m, 1H), 7.71-7.65 (m, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 6.75(brs, 1H), 4.09 (s, 3H), 3.67 (s, 3H), 3.49-3.34 (m, 2H), 3.12-2.95 (m,2H), 2.86-2.74 (m, 1H), 2.54 (s, 3H), 2.40-2.28 (m, 1H), 2.16-1.98 (m,1H), 1.86-1.81 (m, 1H). LC-MS: [M+H]⁺=497.3.

To a mixture of methyl2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)isonicotinate(177-5) (600 mg, 1.21 mmol, 1.0 eq.) and LiCl (512 mg, 12.1 mmol, 10eq.) in MeOH/THF (20 mL, v/v=1/1) was added NaBH₄ (914 mg, 24.2 mmol, 20eq.). The mixture was stirred at 25° C. for 1 hour. The reaction wasquenched with water (50 mL), and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated in vacuoto give methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamate(177-6). LC-MS: [M+H]⁺=469.1.

To a solution of methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(6-methylpyridin-2-yl)piperidin-3-yl)carbamate(177-6) (500 mg, 1.07 mmol, 1.0 eq.), Intermediate B (537 mg, 1.60 mmol,1.5 eq.) and Bu₃P (324 mg, 1.60 mmol, 1.5 eq.) in THF (10 mL) was addedDIAD (324 mg, 1.60 mmol, 1.5 eq.). The mixture was stirred at 25° C. for3 hours. The reaction was concentrated in vacuo and the residue waspurified by silica gel column chromatography (Eluents: PE/EA 10/1 to3:1) to give tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(177-7). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.96 (s, 1H), 8.53 (s, 1H), 8.25(s, 1H), 7.70-7.57 (m, 2H), 7.50-7.43 (m, 1H), 7.36 (d, J=8.0 Hz, 1H),7.20-7.11 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.51 (s, 1H), 5.84 (d, J=15.6Hz, 1H), 5.45 (d, J=15.2 Hz, 1H), 3.64-3.56 (m, 1H), 3.55 (s, 3H),3.53-3.46 (m, 1H), 3.17-3.09 (m, 1H), 3.02-2.94 (m, 1H), 2.66-2.58 (m,1H), 2.57 (s, 3H), 2.48-2.37 (m, 1H), 2.19-2.05 (m, 1H), 1.94-1.84 (m,1H), 1.47 (s, 18H). LC-MS: [M+H]⁺=786.3.

Intermediate 269-4: 3-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine

To a solution of 4-bromo-1H-pyrazole (10.0 g, 68 mmol, 1.0 eq) in DMF(100 mL) was added NaH (5.44 g, 136 mmol, 1.5 eq) at 10° C. After 30min, MeI (15.0 g, 102 mmol, 2.0 eq) was add. The mixture was stirred at30-35° C. for 2 hr, quenched with water (200 mL) and extracted withEtOAc (200 mL×3). The combined organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give 4-bromo-1-methyl-1H-pyrazole (269-1). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43 (s, 1H), 7.37 (s, 1H), 3.88 (s, 3H).

To a solution of 4-bromo-1-methyl-1H-pyrazole (269-1) (10.6 g, 66.1mmol, 1.1 eq) in THF (140 mL) was added n-BuLi (29.4 mL, 72.1 mmol, 1.2eq, 2.5 M in THF) at −70° C. under N₂. After 30 min, a solution ofbenzyl 3-oxopiperidine-1-carboxylate (14.0 g, 60.1 mmol, 1.0 eq) in THF(10 mL) was added. The reaction was stirred at −70° C. for 2 hr. Thereaction was quenched with water (200 mL), extracted with EtOAc (200mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by combi flash (70-90%EtOAc in PE) to give benzyl3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (269-2).LC-MS: [M+H]⁺=316.1.

To a mixture of NaN₃ (1.3 g, 19 mmol, 2.0 eq.) in DCM (30 mL) was addedTFA (6.00 g, 47.6 mmol, 5.0 eq) at 0° C. After 10 min, a solution ofbenzyl 3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate(intermediate 269-2) (3.00 g, 9.52 mmol, 1.0 eq.) in DCM (10 mL) wasadded. The resulting mixture was stirred at 30-35° C. for 16 hr. Thereaction was quenched with NH₃.H₂O (3 mL), diluted with water (20 mL)and extracted with DCM (300 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by Combi Flash (40% EtOAc in PE) to give benzyl3-azido-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (269-3).LC-MS: [M+H]⁺=341.1.

A mixture of benzyl3-azido-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (269-3)(1.00 g, 2.9 mmol, 1.0 eq.) and Pd/C (100 mg, 10% wet) in EtOAc (10 mL)was stirred with H₂ balloon at 30-35° C. for 16 hr. The Pd/C wasfiltered off and the filtrate was concentrated in vacuo to give3-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine (Intermediate 269-4).

Intermediate 269-6: methyl2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)isonicotinate

Methyl5-(3-amino-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(Intermediate 269-5) was prepared following procedures analogous to thepreparation of Intermediate 177-5 and corresponding intermediates. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.46 (s, 1H), 7.88 (s, 1H), 7.75-7.85 (m,1H), 7.65-7.70 (m, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.15-7.25 (m, 1H),3.97 (s, 3H), 3.89 (s, 3H), 3.10-3.30 (m, 3H), 2.90-3.00 (m, 1H),2.05-2.15 (m, 1H), 1.65-1.90 (m, 3H).

To a solution of Intermediate 269-5 (500 mg, 1.17 mmol, 1.0 eq) and Et₃N(400 mg, 3.51 mmol, 3.0 eq) in THF (10 mL) was added methylcarbonochloridate (200 mg, 1.75 mmol, 1.5 eq) at 0° C. The reaction wasstirred at 25-30° C. for 1 hr. The reaction was quenched with water (50mL), extracted with EtOAc (50 mL×3). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycombi flash (60% EtOAc in PE) to give Intermediate 269-6. ¹H NMR (400MHz, CDCl₃) δ ppm 8.51 (s, 1H), 7.95 (s, 1H), 7.80-7.90 (m, 1H),7.60-7.70 (m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.15-7.25 (m, 1H), 6.66(brs, 1H), 4.03 (s, 3H), 3.85 (s, 3H), 3.64 (s, 3H), 3.30-3.40 (m, 2H),2.85-3.10 (m, 2H), 2.80 (d, J=12.0 Hz, 1H), 1.95-2.05 (m, 1H), 1.60-1.85(m, 2H). LC-MS: [M+H]⁺=486.3.

Intermediate 269-8: tert-butyl(tert-butoxycarbonyl)(1-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

Methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)carbamate(Intermediate 269-7) was prepared following procedures analogous to thepreparation of Intermediate 177-6 and corresponding intermediates.LC-MS: [M+H]⁺=458.2.

Intermediate 269-8 was prepared by using a procedure similar to that ofintermediate 177-7 in example 177 by replacing intermediate 177-6 withintermediate 269-7. LC-MS: [M+H]⁺=717.4.

Intermediate 271-7: 3-(pyridin-3-yl)piperidin-3-amine

To a solution of nicotinaldehyde (17.85 g, 166.7 mmol, 1.0 eq.) in THF(250 mL) at −78° C. under N₂ atmosphere was added a solution of3-butenylmagesium bromide (400 mL, 200 mmol, 0.5M, 1.2 eq.) dropwise.The reaction mixture was stirred at −78° C. for 2 h, quenched withsaturated ammonium chloride solution (300 mL) and separated. The aqueouslayer was extracted with ethyl acetate (100 mL*2). The combined organiclayer was washed with brine (200 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo The residue was purified byCombi-flash (EA in PE: 30-50%) to give 1-(pyridin-3-yl)pent-4-en-1-ol(271-1). ¹HNMR (CDCl₃ 400 MHz): δ 8.55 (d, J=1.6 Hz, 1H), 8.51 (dd,J=1.6 Hz and 4.8 Hz, 1H), 7.71 (dt, J=8.0 Hz and 2.0 Hz, 1H), 7.29 (dd,J=4.8 Hz and 8.0 Hz, 1H), 5.90-5.79 (m, 1H), 5.06 (dd, J=1.6 Hz and 17.2Hz, 1H), 5.02 (dd, J=1.2 Hz and 10.4 Hz, 1H), 4.77 (dd, J=5.6 Hz and 8.0Hz), 2.34 (brs, 1H), 2.24-2.10 (m, 2H), 1.98-1.88 (m, 1H), 1.86-1.77 (m,1H).

To a solution of 1-(pyridin-3-yl)pent-4-en-1-ol (271-1) (10 g, 61.27mmol, 1 eq) in CH₂Cl₂ (200 mL) was added Dess-Martin periodinane (38.98g, 91.9 mmol, 1.5 eq) portionwise at 16-24° C., the suspension wasstirred for 30 min at 16-24° C. The mixture was poured into a saturatedsodium bicarbonate solution (300 mL) slowed and stirred for 30 min. Themixture was filtered and aqueous layer was extracted with CH₂Cl₂ (100mL*2). The combined organic layer was washed with brine (100 mL), driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by Combi-flash (EA in PE: 20-30%) to give1-(pyridin-3-yl)pent-4-en-1-one (271-2). ¹H NMR (CDCl₃400 MHz): δ 9.18(d, J=1.6 Hz, 1H), 8.78 (dd, J=1.6 Hz and 4.8 Hz, 1H), 8.23 (dt, J=8.0Hz and 2.0 Hz, 1H), 7.43 (dd, J=4.8 Hz and 8.0 Hz, 1H), 5.94-5.84 (m,1H), 5.12-5.06 (m, 1H), 5.05-5.01 (m, 1H), 2.10 (t, J=7.2 Hz, 2H),2.55-2.48 (m, 2H).

To a mixture of 1-(pyridin-3-yl)pent-4-en-1-one (271-2) (8.64 g, 53.6mmol, 1eq) and 2-methylpropane-2-sulfinamide (12.99 g, 107.2 mmol, 2.0eq) in anhydrous THF (120 ml) was added titanium ethoxide (30.57 g,134.0 mmol, 2.5 eq), the reaction mixture was refluxed for 16 h at 80°C. The mixture was cooled to room temperature, poured into brine (300ml) and stirred for 30 min. The mixture was filtered through a celitepad and the aqueous layer was extracted with ethyl acetate (200 mL*2).The combined organic layer was washed with brine (200 mL), dried overanhydrous sodium sulfate and concentrated. The residue was purified byCombi-flash (EA in PE: 20-30%) to give(E)-2-methyl-N-(1-(pyridin-3-yl)pent-4-en-1-ylidene)propane-2-sulfinamide(271-3). ¹H NMR (CDCl₃ 400 MHz): δ 9.05 (s, 1H), 8.70 (dd, J=1.6 Hz and4.8 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.38 (dd, J=4.8 Hz and 8.0 Hz, 1H),5.93-5.81 (m, 1H), 5.09-5.01 (m, 2H), 3.45-3.37 (m, 1H), 3.32-3.25 (m,1H), 2.55-2.35 (m, 2H).

To a solution of(E)-2-methyl-N-(1-(pyridin-3-yl)pent-4-en-1-ylidene)propane-2-sulfinamide(271-3) (9.85 g, 37.3 mmol, 1eq) in anhydrous THF (120 mL) at −78° C.was added a solution of vinylmagnesium bromide (90 mL, 90 mmol, 2.4eq,1M in Et₂O) dropwise, the resulting mixture was stirred for 2 h at −78°C. The reaction was quenched with saturated ammonium chloride (200 mL).The mixture was extracted with ethyl acetate (100 mL*3), the combinedorganic layer was washed with brine (100 ml), dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified byCombi-flash (EA in PE: 30-70%) to give2-methyl-N-(3-(pyridin-3-yl)hepta-1,6-dien-3-yl)propane-2-sulfinamide(271-4). ¹H NMR (CDCl₃ 400 MHz): δ 8.89 (d, J=1.6 Hz, 1H), 8.53 (dd,J=1.6 Hz and 4.8 Hz, 1H), 7.82-7.78 (m, 1H), 7.29 (dd, J=4.8 Hz and 8.0Hz, 1H), 6.03 (dd, J=10.8 Hz and 17.2 Hz, 1H), 5.87-5.78 (m, 1H), 5.37(d, J=10.8 Hz, 1H), 5.30 (d, J=17.2 Hz, 1H), 5.05-4.96 (m, 2H), 3.75 (s,1H), 2.43-2.35 (m, 1H), 2.26-2.18 (m, 1H), 2.07-1.97 (m, 2H), 1.24 (s,9H).

To a solution of2-methyl-N-(3-(pyridin-3-yl)hepta-1,6-dien-3-yl)propane-2-sulfinamide(271-4) (6.90 g, 23.6 mmol, 1.0 eq) in methanol (400 ml) at −78° C. wasbubbled O₃ until the solution was blue. The excess O₃ was removed by N₂.The mixture was concentrated in vacuo to remove about 200 mL ofmethanol. Diphenylmethanylamine (6.48 g, 35.4 mmol, 1.5 eq), sodiumcyanoborohydride (3.72 g, 59.0 mmol, 2.5 eq) and acetic acid (1.42 g,23.6 mmol, 1.0 eq) were added to the above solution and the reactionmixture was stirred for 16 h at 11-17° C.

The mixture was concentrated in vacuo, the residue was diluted eithwater (100 mL) and extracted with dichloromethane (100 ml*3). Thecombined organic layer was concentrated in vacuo, the residue waspurified by Combi-flash (EA in PE: 30-100%) to giveN-(1-benzhydryl-3-(pyridin-3-yl)piperidin-3-yl)-2-methylpropane-2-sulfinamide(271-6). ¹H NMR (CDCl₃ 400 MHz): δ 8.57 (d, J=2.0 Hz, 1H), 8.47 (dd,J=1.6 Hz and 4.8 Hz, 1H), 7.64 (dt, J=8.0 Hz and 1.6 Hz, 1H), 7.40-7.37(m, 4H), 7.33-7.28 (m, 4H), 7.25-7.20 (m, 3H), 5.53 (brs, 1H), 4.39 (s,1H), 3.06-2.99 (m, 2H), 2.58 (d, J=12.8 Hz, 1H), 2.33-2.25 (m, 1H),2.09-2.01 (m, 1H), 1.96-1.89 (m, 2H), 1.77-1.73 (m, 1H), 1.28 (s, 9H).LC-MS: M+H]⁺=448.2.

To a solution ofN-(1-benzhydryl-3-(pyridin-3-yl)piperidin-3-yl)-2-methylpropane-2-sulfinamide(271-6) (2.34 g, 5.23 mmol, 1.0 eq.) in TFA (24 mL) was added Et₃SiH(4.68 mL), the reaction mixture was stirred for 16 h at 80° C. Themixture was concentrated in vacuo, the residue was diluted with water(50 mL) and extracted with ethyl acetate (30 mL*2) to remove impurities.The aqueous layer was neutralized with sodium hydroxide and concentratedin vacuo to give crude 3-(pyridin-3-yl)piperidin-3-amine (Intermediate217-7). LC-MS: [M+H]⁺=177.9.

Intermediate 271-9:(5-(3-amino-3-(pyridin-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methanol

Methyl5-(3-amino-3-(pyridin-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(Intermediate 271-8) was prepared following procedures analogous to thepreparation of Intermediate 177-5 and corresponding intermediates. ¹HNMR (CDCl₃ 400 MHz): δ 8.90 (d, J=2.0 Hz, 1H), 8.54 (dd, J=1.6 Hz and4.8 Hz, 1H), 8.46 (s, 1H), 7.98 (dt, J=8.0 Hz and 1.6 Hz, 1H), 7.88 (s,1H), 7.85-7.79 (m, 1H), 7.69-7.66 (m, 1H), 7.30 (dd, J=4.8 Hz and 8.0Hz, 1H), 7.24-7.19 (m, 1H), 3.97 (s, 3H), 3.34-3.23 (m, 3H), 2.97 (td,J=12 Hz and 2.4 Hz, 1H), 2.21-2.15 (m, 1H), 2.08 (dt, J=12.8 Hz and 4.4Hz, 1H), 1.88-1.84 (m, 1H), 1.82-1.76 (m, 1H). LC-MS: [M+H]⁺=425.2,

Intermediate 271-9 was prepared by using a procedure similar to that ofintermediate 177-6 in Example 177 by replacing intermediate 177-5 withintermediate 271-8. ¹H NMR (CDCl₃ 400 MHz): δ 8.81 (d, J=2.0 Hz, 1H),8.52 (dd, J=1.6 Hz and 4.8 Hz, 1H), 8.41 (s, 1H), 7.88 (dt, J=8.0 Hz and1.6 Hz, 1H), 7.85-7.79 (m, 1H), 7.71 (s, 1H), 7.69-7.66 (m, 1H), 7.30(dd, J=4.8 Hz and 8.0 Hz, 1H), 7.25-7.18 (m, 1H), 4.92 (d, J=14 Hz, 1H),4.73 (d, J=14 Hz, 1H), 3.20 (t, J=11.6 Hz, 2H), 3.09 (d, J=11.6 Hz, 1H),3.01-2.94 (m, 1H), 2.14-2.08 (m, 2H), 1.92-1.87 (m, 2H). LC-MS:[M+H]⁺=397.3.

Intermediate 272-2: 1-Benzyl 3-methyl 2-oxopiperidine-1,3-dicarboxylate

To a solution of piperidin-2-one (10 g, 100 mmol, 1.0 eq) in dry THF(200 mL) was added portions NaH (6 g, 60% wt, 150 mmol, 1.5 eq) below 0°C. The resulting mixture was stirred at 0° for 0.5 h and 30° C. for 1 h.Then a solution of benzyl carbonochloridate (26 g, 151.31 mmol, 1.5 eq)in dry THF (50 mL) was added into the suspension below 0° C. over 30min. The resulting mixture was stirred at 30° C. for 3 h. The reactionwas quenched by Sat. NH₄Cl (50 mL), extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine (50 mL) and dried overNa₂SO₄. After filtration and concentration, the residue was purified bysilica gel chromatography to give benzyl 2-oxopiperidine-1-carboxylate(272-1). ¹H NMR (CDCl₃, 400 MHz): δ ppm 7.45-7.32 (m, 5H), 5.28 (s, 2H),3.78-3.70 (m, 2H), 2.56-2.50 (m, 2H), 1.86-1.80 (m, 4H).

To a solution of benzyl 2-oxopiperidine-1-carboxylate (272-1) (9.1 g,39.1 mmol, 1.0 eq) in dry THF (200 mL) was added LDA (30 mL, 2M, 60mmol, 1.54 eq) below −70° C. over 30 min under N₂. After stirring for 1h at −70°, methyl carbonochloridate (6.23 g, 65.93 mmol, 1.69 eq) wasadded into the mixture below −70° C. over 30 min. The resulting mixturewas stirred at −70° C. for 1 h. The reaction mixture was quenched bySat. NH₄Cl (50 mL) below −70° C. The mixture was extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine (100 mL)and dried over Na₂SO₄. After filtration and concentration, the residuewas purified by inversed phase chromatography to give 1-benzyl 3-methyl2-oxopiperidine-1,3-dicarboxylate (Intermediate 272-2). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.45-7.32 (m, 2H), 5.29 (s, 2H), 3.80-3.79 (d, J=5.2 Hz,1H), 3.77 (s, 3H), 3.76-3.74 (d, J=7.6 Hz, 1H), 3.58-3.54 (dd, J=6.8 Hz,J=8.0 Hz, 1H), 2.30-2.16 (m, 1H), 2.14-2.06 (m, 2H), 2.02-1.93 (m, 1H).

Intermediate 272-3: (2-methoxypyridin-3-yl)boronic acid

A suspension 3-bromo-2-methoxypyridine (9 g, 47.87 mmol, 1.0 eq), Mg(2.33 g, 95.73 mmol, 2.0 eq) and LiCl (2.54 g, 59.83 mmol, 1.25 eq) indry THF (200 mL) was stirred at 35° C. for 2 hours under N₂. ThenB(OMe)₃ (10 g, 96.23 mmol, 2.01 eq) was added into the reaction mixturebelow 0° C. Then resulting mixture was allowed to warm to 35° C. withstirring for 2 hours. The reaction was quenched with HCl (0.1M, 200 mL)to pH=6. The mixture was extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine (100 mL) and dried over Na₂SO₄.After filtration and concentration, the residue was washed withchloroform (10 mL) to give (2-methoxypyridin-3-yl)boronic acid(Intermediate 272-3). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.19-8.17 (dd,J₁=2.0 Hz, J₂=4.8 Hz, 1H), 7.89-7.88 (d, J=2.0 Hz, 1H), 3.98-6.95 (dd,J₁=4.8 Hz, J₂=6.8 Hz, 1H), 3.87 (s, 3H).

Intermediate 272-5: 1-Benzyl 3-methyl3-(2-methoxypyridin-3-yl)-2-oxopiperidine-1,3-dicarboxylate

To a suspension of Pb(OAc)₄ (6.38 g, 14.39 mmol, 1.0 eq) and Hg(OAc)₂(1.17 g, 3.67 mmol, 0.26 eq) in chloroform (20 mL) was added(2-methoxypyridin-3-yl)boronic acid (272-3) (2.2 g, 14.38 mmol. 1.0 eq)at 30° C. under N₂. The suspension was stirred at 40° C. for 1 hour and30° for 16 hours under N₂. The reaction mixture of(2-methoxypyridin-3-yl)plumbanetriyl triacetate (272-4) was used in thenext step directly. Then a solution of 1-benzyl 3-methyl2-oxopiperidine-1,3-dicarboxylate (272-2) (3.9 g, 13.23 mmol, 0.93 eq)in chloroform (20 mL) and pyridine (3 mL) was added into the suspension.The resulting mixture was stirred at 40° C. for 12 hours under N₂. LC-MSshowed intermediate 272-4 was consumed. The reaction mixture was cooledto room temperature and filtrated. The filtrate was washed with H₂SO₄(1M, 20 mL×4), water (20 mL×2) and dried over Na₂SO₄. After filtrationand concentration, the residue was purified by Prep-HPLC (FA) to give1-benzyl 3-methyl3-(2-methoxypyridin-3-yl)-2-oxopiperidine-1,3-dicarboxylate(Intermediate 272-5). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12-8.11 (m, 1H),7.45-7.44 (m, 2H), 7.40-7.31 (m, 4H), 6.88-6.85 (m, 1H), 5.33 (s, 2H),3.91 (s, 3H), 3.88-3.85 (m, 1H), 3.79 (s, 3H), 3.76-3.69 (m, 1H),2.66-2.60 (m, 1H), 2.56-2.50 (m, 1H), 1.90-1.82 (m, 1H), 1.77-1.68 (m,1H). LC-MS: [M+H]⁺=398.9.

Intermediate 272-10:Methyl(3-(2-methoxypyridin-3-yl)piperidin-3-yl)carbamate

To a solution of 1-benzyl 3-methyl3-(2-methoxypyridin-3-yl)-2-oxopiperidine-1,3-dicarboxylate(Intermediate 272-5) (1.7 g, 4.27 mmol, 1.0 eq) in dry THF (50 mL) anddry THF (50 mL) was added NaBH₄ (0.3 g, 7.93 mmol, 1.86 eq) below 0° C.After addition, the reaction mixture was allowed to stir at 30° C. for 2hours. Then Pd/C (0.45 g, 0.427 mmol, 0.1 eq) was added into themixture, the resulting mixture was stirred at 30° C. under H₂ (15 Psi)for 12 hours. The mixture was filtered, the filtrate was concentratedunder reduced pressure to afford methyl3-(2-methoxypyridin-3-yl)piperidine-3-carboxylate (272-6).

To a solution of methyl3-(2-methoxypyridin-3-yl)piperidine-3-carboxylate (272-6) (2.2 g, 8.79mmol, 1.0 eq) and Boc₂O (5.75 g, 26.37 mmol, 3.0 eq) in MeOH (10 mL) wasstirred at 30° C. for 16 hours. The reaction mixture was concentrated,and the residue was purified by silica gel chromatography to give1-(tert-butyl) 3-methyl3-(2-methoxypyridin-3-yl)piperidine-1,3-dicarboxylate (272-7). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.08-8.07 (d, J=4.0 Hz, 1H), 7.63-7.61 (dd,J₁=1.6 Hz, J₂=8.6 Hz, 1H), 6.90-6.86 (dd, J₁=5.2 Hz, J₂=7.6 Hz, 1H),4.15-4.10 (m, 1H), 3.92 (s, 3H), 3.82-3.66 (m, 2H), 3.61 (s, 3H), 3.22(m, 1H), 2.23-2.19 (m, 2H), 1.71 (m, 4H), 1.32 (s, 9H). LC-MS:[M+H]⁺=351.0.

A solution of 1-(tert-butyl) 3-methyl3-(2-methoxypyridin-3-yl)piperidine-1,3-dicarboxylate (272-7) (0.85 g,2.43 mmol, 1.0 eq) and LiOH (0.233 g, 9.70 mmol, 4.0 eq) in MeOH (10 mL)and H₂O (2 mL) was heated to 40° C. with stirring for 2 hours and 80° C.for 4 hours. The reaction mixture was concentrated, the residue wasacidified with HCl (2N) to pH=3-4. The mixture was extracted withchloroform/i-PrOH (v/v=3:1, 10 mL×4). The combined organic layers werewashed with water (10 mL) and dried over Na₂SO₄. The mixture wasfilteredans the filtrate was concentrated to give1-(tert-butoxycarbonyl)-3-(2-methoxypyridin-3-yl)piperidine-3-carboxylicacid (272-8). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.05-8.04 (d, J=3.2 Hz, 1H),7.75-7.73 (dd, J₁=1.6 Hz, J₂=7.2 Hz, 1H), 6.96 (s, 1H), 4.14-4.10 (m,1H), 4.10-3.89 (m, 4H), 3.62-3.58 (m, 1H), 3.30-3.28 (m, 1H), 2.33-2.28(m, 2H), 1.83-1.79 (m, 2H), 1.27 (s, 9H).

To a solution of1-(tert-butoxycarbonyl)-3-(2-methoxypyridin-3-yl)piperidine-3-carboxylicacid (272-8) (0.8 g, 2.38 mmol, 1.0 eq) in dry toluene (20 mL) was addedDPPA (1.31 g, 4.76 mmol, 2.0 eq) and TEA (0.963 g, 9.51 mmol, 4.0 eq) inturns at 28° C. under N₂. The mixture was stirred at 80° C. for 12hours. Then MeOH (20 mL) was added into the mixture and the mixture wasstirred at 80° C. for 12 hours. The mixture was concentrated underreduced pressure and the residue was purified by silica gelchromatography to tert-butyl3-((methoxycarbonyl)amino)-3-(2-methoxypyridin-3-yl)piperidine-1-carboxylate(272-9). ¹H NMR (400 MHz, CDCl₃) b ppm 8.098.074 (dd, J₁=2.0 Hz, J₂=5.2Hz, 1H), 7.67-7.64 (dd, J₁=1.6 Hz, J₂=7.6 Hz, 1H), 6.92-6.88 (dd, J₁=4.8Hz, J₂=7.6 Hz, 1H), 5.78-5.49 (m, 1H), 4.72-4.68 (d, 13.6 Hz, 1H), 3.99(s, 3H), 3.53 (s, 3H), 2.98-2.80 (m, 3H), 1.91-1.71 (m, 4H), 1.83 (s,9H).

To a solution of tert-butyl3-((methoxycarbonyl)amino)-3-(2-methoxypyridin-3-yl)piperidine-1-carboxylate(272-9) (0.6 g, 1.64 mmol, 1.0 eq) in dry DCM (5 mL) was added TFA (1mL) below 0° C. After addition, the mixture was allowed to warm to 30°C. with stirring for 3 hours. The mixture was concentrated under reducedpressure to methyl (3-(2-methoxypyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 272-10). LC-MS: [M+H]⁺=266.2.

Intermediate 272-13: tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(2-methoxypyridin-3-yl)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

Intermediate 272-13 was prepared following procedures analogous to thepreparation of Intermediate 177-7 and corresponding intermediates. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.93 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H),8.14-8.12 (dd, J₁=1.6 Hz, J₂=5.2 Hz, 1H), 7.77-7.75 (dd, J₁=1.6 Hz,J₂=7.6 Hz, 1H), 7.70-7.64 (m, 1H), 7.48-7.46 (m, 1H), 7.20-7.13 (dd,J₁=5.2 Hz, J₂=7.6 Hz, 1H), 6.60 (s, 1H), 5.89-5.85 (d, J=15.6 Hz, 1H),5.43-5.39 (d, J=15.6 Hz, 1H), 4.04-4.01 (m, 1H), 3.98 (s, 3H), 3.49 (s,3H), 3.36-3.34 (m, 1H), 3.14-3.11 (m, 1H), 2.94-2.84 (m, 2H), 2.21-2.18(m, 2H), 1.88-1.85 (m, 1H), 1.47 (s, 18H). LC-MS: [M+H]⁺=802.5.

Intermediate 273-5a: tert-Butyl3-cyano-3-(1-(difluoromethyl)-1H-pyrazol-3-yl)piperidine-1-carboxylateIntermediate 273-5b: tert-Butyl3-cyano-3-(1-(difluoromethyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl 3-cyanopiperidine-1-carboxylate (25 g, 119.0mmol, 1.0 eq.) in THF (300 mL) at −70° C. under N₂ atmosphere was addedLiHMDS (178 mL, 178.57 mmol, 1.5 eq.) dropwise. The reaction mixture wasstirred at −70° C. for 30 min, then CH₃CHO (7.85 g, 178.57 mmol, 3 eq.)was added. The reaction was quenched with aq.NH₄Cl (200 mL), extractedwith EtOAc (100 mL*3). The combined organic layer was washed with brine(200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by Combi-flash (EtOAc in PE,10-50%) to give tert-butyl3-cyano-3-(1-hydroxyethyl)piperidine-1-carboxylate (273-1). ¹H NMR(CDCl₃ 400 MHz): δ ppm 4.39-4.05 (m, 2H), 3.75-3.68 (m, 2H), 2.94-2.76(m, 2H), 2.39-2.20 (m, 1H), 1.94-1.70 (m, 4H), 1.47 (s, 9H), 1.39 (t,J=6.4 Hz, 3H).

To a solution of tert-butyl3-cyano-3-(1-hydroxyethyl)piperidine-1-carboxylate (273-1) (9 g, 35.43mmol, 1.0 eq.) in DCM (150 mL) was added DMP (22.5 g, 53.15 mmol, 1.5eq.). The mixture was stirred at 20° C. for 1 hour. The reaction wasquenched with aq.NaHCO₃ (150 mL) and aq.Na₂SO₃ (150 mL), extracted withEtOAc (150 mL*3). The combined organic layers were washed with aq.NaHCO₃(150 mL), dried over anhydrous sodium sulfate, filtered and concentratedto give crude tert-butyl 3-acetyl-3-cyanopiperidine-1-carboxylate(273-2). ¹H NMR (CDCl₃ 400 MHz): δ 4.50-3.85 (m, 2H), 3.20-3.05 (m, 1H),2.95-2.60 (m, 1H), 2.46 (s, 3H), 2.25-1.70 (m, 4H), 1.48 (s, 9H).

To a solution of tert-butyl 3-acetyl-3-cyanopiperidine-1-carboxylate(273-2) (12 g, 47.62 mmol, 1.0 eq.) in toluene (100 mL) was addedDMF-DMA (28.3 g, 238.1 mmol, 5.0 eq.). The reaction was heated to 100°C. and stirred for 2 h. LC-MS showed a main product. The reaction wasconcentrated to give tert-butyl(E)-3-cyano-3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate(273-3). LCMS: [M+H]+=308.0.

A mixture of tert-butyl(E)-3-cyano-3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate(273-3) (5.6 g, 18.22 mmol) in EtOH (30 mL), was added hydrazine hydrate(8.85 mL, 182 mmol), then the mixture was stirred at 70° C. for 8 hrunder Ar atmosphere. Water (50 ml) was added, the mixture was extractedwith EtOAc, the combined organic phase was worked up under aqueousconditions and concentrated in vacuo. The residue was purified by flashchromatography (PE/EA, EA: 40% for 30 mins) to give tert-butyl3-cyano-3-(1H-pyrazol-3-yl)piperidine-1-carboxylate (273-4). ¹H NMR (400MHz, CDCl₃) δ ppm 7.63 (d, J=2.0 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H),4.56-4.46 (m, 1H), 4.25-4.07 (m, 1H), 3.20 (d, J=12.0 Hz, 1H), 2.80-2.90(m, 1H), 2.37 (d, J=13.2 Hz, 1H), 2.10-1.91 (m, 2H), 1.77 (d, J=11.0 Hz,1H), 1.48 (s, 9H).

To a solution of tert-butyl3-cyano-3-(1H-pyrazol-3-yl)piperidine-1-carboxylate (273-4) (500 mg,1.809 mmol) and Cs₂CO₃ (2948 mg, 9.05 mmol) in DMF (10 mL), was addedmethyl 2-chloro-2,2-difluoroacetate (523 mg, 3.62 mmol) dropwise, andthe reaction mixture was stirred at 60° C. for 24 hr. The reactionmixture was diluted with ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was dried over sodiumsulfate, and concentrated in vacuum, the residue was purified by flashchromatography (PE/EA, EA: 40% for 30 mins) to give tert-butyl3-cyano-3-(1-(difluoromethyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate(Intermediate 273-5a) and tert-butyl3-cyano-3-(1-(difluoromethyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate(Intermediate 273-5b). LC-MS: [M−100]⁺=227.1.

Intermediate 273-11: tert-Butyltert-butoxycarbonyl(9-((5-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-3-((methoxycarbonyl)amino)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

Intermediate 273-11 was prepared following procedures analogous to thepreparation of Intermediate 177-7 and corresponding intermediates.LC-MS: [M+H]⁺=792.3

Intermediate 281-7: Benzyl3-carbamoyl-3-(2-chlorothiazol-4-yl)piperidine-1-carboxylate

A solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (20 g,72.12 mmol, 1.0 eq) in THF (120 mL) was cooled to −78° C. and a solutionof LiHMDS (108.18 mL, 108.18 mmol, 1.5 eq) was added dropwise over 20minutes, and then stirred at −78° C. for 30 minutes, followed by theaddition of CH₃CHO (3.81 g, 86.54 mmol, 1.2 eq). The resulting mixturewas then stirred at 32° C. for 1 hour. The mixture was quenched withsaturated NH₄Cl solution (150 mL), extracted with EtOAc (200 mL*3). Thecombined organic phase was washed with brine (400 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by flash column (Petroleum ether:EtOAc=9:1-5:1) to give1-benzyl 3-methyl 3-(1-hydroxyethyl)piperidine-1,3-dicarboxylate(281-1). ¹H NMR (CDCl₃ 400 MHz): δ 7.36-7.28 (m, 5H), 5.12 (s, 2H),4.04-3.92 (m, 1H), 3.84-3.77 (m, 1H), 3.66-3.46 (m, 4H), 3.29-3.20 (m,1H), 3.11-2.92 (m, 1H), 2.09-1.99 (m, 1H), 1.84-1.79 (m, 1H), 1.70-1.63(m, 1H), 1.54-1.36 (m, 1H), 1.16 (d, J=6.4 Hz, 3H).

To a mixture of 1-benzyl 3-methyl3-(1-hydroxyethyl)piperidine-1,3-dicarboxylate (281-1) (17 g, 52.9 mmol,1.0 eq.) in CH₂Cl₂ (300 mL) was added Dess-Martin reagent (29.2 g, 68.8mmol, 1.3 eq) in portions over 10 minutes at 0° C. Then, the mixture wasstirred at 32° C. for 2 hours.

The mixture was quenched with saturated NaHCO₃ solution (300 mL) andstirred for 30 minutes until pH to 8, diluted with CH₂Cl₂ (300 mL),continued to stirred for 30 minutes, filtered, separated andconcentrated the organic phase. The crude was purified by flash column(Petroleum ether:EtOAc=10:1) to give 1-benzyl 3-methyl3-acetylpiperidine-1,3-dicarboxylate (281-2). ¹H NMR (CDCl₃ 400 MHz):6.7.34-7.28 (m, 5H), 5.11 (s, 2H), 4.20-3.16 (m, 7H), 2.28-1.84 (m, 5H),1.76-1.59 (m, 2H).

To a solution of 1-benzyl 3-methyl 3-acetylpiperidine-1,3-dicarboxylate(intermediate 281-2) (15.0 g, 46.9 mmol, 1.0 eq.) in MeOH (200 mL) wasadded Br₂ (2.6 ml, 51.67 mmol, 1.1 eq) in portions over 5 minutes. Theresulting mixture was stirred at 60° C. for 1.5 hours. The mixture wasconcentrated and the crude was diluted with EtOAc (300 mL), washed withsaturated Na₂SO₃ solution (300 mL), dried over anhydrous sodium sulfate,filtered and concentrated to give 1-benzyl 3-methyl3-(2-bromoacetyl)piperidine-1,3-dicarboxylate (281-3). LCMS:[M+H]⁺=399.9.

To a mixture of 1-benzyl 3-methyl3-(2-bromoacetyl)piperidine-1,3-dicarboxylate (281-3) (16 g, 32.14 mmol,1.0 eq) and thiourea (4.89 g, 64.28 mmol, 2.0 eq) in EtOH (200 mL) wasadded NaHCO₃ (5.40 g, 64.28 mmol, 2.0 eq). The resulting mixture washeated at 90° C. for 1.5 hours with stirring, and the mixture wasconcentrated in vacuum. The residue was dissolved in EtOAc (300 mL),washed with saturated brine (300 mL*3), dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified by flashcolumn (petroleum ether:EtOAc=8:1-1:1) to give 1-benzyl 3-methyl3-(2-aminothiazol-4-yl)piperidine-1,3-dicarboxylate (281-4). ¹H NMR(CDCl₃ 400 MHz): 6.7.41-7.30 (m, 5H), 6.41-6.23 (m, 1H), 5.53-5.47 (m,2H), 5.16 (s, 2H), 4.36-4.09 (m, 2H), 3.77-3.68 (m, 1H), 3.62-3.59 (m,3H), 3.54-3.48 (m, 1H), 3.37-3.18 (m, 1H), 2.40-2.25 (m, 2H), 2.12-2.01(m, 1H), 1.61-1.55 (m, 2H).

To a solution of 1-benzyl 3-methyl3-(2-aminothiazol-4-yl)piperidine-1,3-dicarboxylate (281-4) (5 g2, 13.32mmol2, 1.0 eq) in CH₃CN (50 mL) was added CuCl (3.30 g, 33.29 mmol, 2.5eq) and heated to 60° C., followed by the addition of t-BuONO (3.43 g,33.29 mmol, 2.5 eq) in portions over 5 minutes. The resulting mixturewas then stirred at 80° C. under nitrogen for 1 hour. The mixture wascooled to 30° C., diluted with water (50 mL), extracted with EtOAc (60ml*3), and the organic phase was washed with brine (200 mL), dried overanhydrous sodium sulfate, filtered and concentrated. Two batches withsame scale was carried out and combined. The crude was purified by flashcolumn (Petroleum ether:EtoAc=15:1˜ 5:1) to give 1-benzyl 3-methyl3-(2-chlorothiazol-4-yl)piperidine-1,3-dicarboxylate (281-5). ¹H NMR(DMSO-d6 400 MHz): δ. 7.57 (s, 1H), 7.37-7.31 (m, 5H), 5.07 (s, 2H),4.28-4.13 (m, 1H), 3.69-3.63 (m, 1H), 3.55 (s, 3H), 3.58-3.51 (m, 1H),3.28-3.18 (m, 1H), 2.32-2.27 (m, 1H), 2.12-2.02 (m, 1H), 1.61-1.42 (m,2H).

To a solution of 1-benzyl 3-methyl3-(2-chlorothiazol-4-yl)piperidine-1,3-dicarboxylate (281-5) (7.0 g,17.73 mmol, 1.0 eq) in MeOH/H₂O (80 mL/10 mL) was added LiOH.H₂O (7.4 g,177.27 mmol, 10.0 eq) and the resulting mixture was stirred at 30° C.for 2.0 hours. The mixture was acidified with 2N HCl to pH 5-6, dilutedwith water (40 mL), extracted with EtOAc (80 mL*3). The combined organicphase was washed with brine (250 mL), dried over anhydrous sodiumsulfate, filtered and concentrated to give1-((benzyloxy)carbonyl)-3-(2-chlorothiazol-4-yl)piperidine-3-carboxylicacid (281-6). LCMS: [M+Na]*=403.0.

To a solution of1-((benzyloxy)carbonyl)-3-(2-chlorothiazol-4-yl)piperidine-3-carboxylicacid (281-6) (5.6 g, 14.70 mmol, 1.0 eq) and NH₄Cl (1.57 g, 29.41 mmol,2.0 eq) in DMF (60 mL) was added DIEA (7.60 g, 58.82 mmol, 4.0 eq) andHATU (11.18 g, 29.41 mmol, 2.0 eq). The resulting mixture was stirred at30° C. for 1 hour and the desired MS was observed by LC-MS. The mixturewas diluted with water (40 mL), extracted with EtOAc (80 mL*3). Thecombined organic phase was washed with brine (200 mL*5), dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified by flash column (Petroleum ether:EtOAc=5:1˜ 1:1) to give benzyl3-carbamoyl-3-(2-chlorothiazol-4-yl)piperidine-1-carboxylate(Intermediate 281-7). ¹H NMR (DMSO-d₆ 400 MHz): δ. 7.44-7.31 (m, 6H),7.13 (s, 1H), 7.01 (s, 1H), 5.06 (s, 2H), 4.07-4.03 (m, 1H), 3.78-3.63(m, 1H), 3.58-3.46 (m, 1H), 3.18 (br s, 1H), 2.33-2.25 (m, 1H),2.13-2.08 (m, 1H), 1.61-1.46 (m, 1H), 1.40-1.29 (m, 1H).

Intermediate 281-10: Methyl5-(3-(2-chlorothiazol-4-yl)-3-((methoxycarbonyl)amino)piperidin-1-yl)-2-(4-fluorophenyl)isonicotinate

Benzyl3-(2-chlorothiazol-4-yl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(Intermediate 281-8) was prepared following procedures analogous to thepreparation of Intermediate 177-3 and corresponding intermediates. ¹HNMR (CDCl₃ 400 MHz): δ. 7.37-7.30 (m, 5H), 7.18-7.07 (m, 1H), 5.44-5.11(m, 3H), 4.23-4.08 (m, 1H), 3.92-3.89 (m, 1H), 3.74-3.56 (m, 4H), 3.14(t, J=10.4 Hz, 1H), 2.71-2.50 (m, 1H), 2.25-2.12 (m, 1H), 1.71-1.65 (m,1H), 1.60-1.49 (m, 1H).

A solution of benzyl3-(2-chlorothiazol-4-yl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(Intermediate 281-8) (1.5 g, 3.66 mmol, 1.0 eq) in TFA (12.0 mL) wasstirred at 66° C. for 4.0 hours. The mixture was concentrated in vacuoand the residue was dissolved in EtOAc (20 mL), washed with saturatedNaHCO₃ solution (40 mL*3), dried over anhydrous sodium sulfate, filteredand concentrated to give methyl(3-(2-chlorothiazol-4-yl)piperidin-3-yl)carbamate (281-9).

To a solution of methyl(3-(2-chlorothiazol-4-yl)piperidin-3-yl)carbamate (281-9) (1.3 g, 3.63mmol, 1.0 eq) and Intermediate C (903.7 mg, 3.63 mmol, 1.0 eq) in DMSO(20 mL) was added DIEPA (1.87 g, 14.51 mmol, 4.0 eq). The reactionmixture was stirred at 120° C. for 12 hours. The desired MS was observedby LCMS. The mixture was cooled to 30° C., diluted with water (20 mL),extracted with EtOAc (30 mL*3). The organic phase was washed with brine(60 mL*3), dried over anhydrous sodium sulfate, filtered andconcentrated. The crude was purified by flash column (Petroleumether:EtOAc=15:1˜ 6:1) to give methyl5-(3-(2-chlorothiazol-4-yl)-3-((methoxycarbonyl)amino)piperidin-1-yl)-2-(4-fluorophenyl)isonicotinate(Intermediate 281-10).

¹H NMR (CDCl₃ 400 MHz): δ. 8.53 (s, 1H), 7.97 (s, 1H), 7.96-7.92 (m,2H), 7.18-7.12 (m, 3H), 6.82 (brs, 1H), 4.04 (s, 3H), 3.66 (s, 3H), 3.50(d, J=12.4 Hz, 1H), 3.32 (d, J=10.0 Hz, 1H), 3.10-2.98 (m, 2H),2.93-2.84 (m, 1H), 2.06-1.95 (m, 2H), 1.87-1.76 (m, 1H).

Intermediate 281-12: tert-Butyl(tert-butoxycarbonyl)(9-((5-(3-(2-chlorothiazol-4-yl)-3-((methoxycarbonyl)amino)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

Methyl(3-(2-chlorothiazol-4-yl)-1-(6-(4-fluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(Intermediate 281-11) was prepared following procedures analogous to thepreparation of Intermediate 177-6. ¹H NMR (CDCl₃ 400 MHz): δ. 8.45 (s,1H), 7.94-7.90 (m, 2H), 7.64 (s, 1H), 7.15-7.11 (m, 3H), 7.15-7.10 (m,2H), 5.75 (brs, 1H), 4.89-4.78 (m, 2H), 3.63 (s, 3H), 3.60-3.56 (m, 1H),3.30-3.26 (m, 1H), 3.15-3.11 (m, 1H), 2.99-2.92 (m, 1H), 2.60-2.57 (m,1H), 2.14-2.07 (m, 1H), 2.00-1.93 (m, 1H), 1.85-1.79 (m, 1H).

Intermediate 281-12 was prepared following procedures analogous to thepreparation of Intermediate 177-7 and corresponding intermediates. LCMS:[M+H]⁺=794.4

Intermediate 282-4: 1-Benzyl 3-methyl3-(2H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate

To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (30 g,108 mmol, 1.0 eq) in THF (350 mL) was added LiHMDS (163 mL, 163 mmol,1.5 eq) dropwise at −65° C. under N₂ atmosphere. After stirred for 30min, paraformaldehyde (9.72 g, 324 mmol, 3.0 eq) was added. The reactionsuspension was stirred at 13-23° C. for 1 hour. The reaction wasquenched with water (300 mL), extracted with EtOAc (300 mL*3), washedwith brine (500 mL*2). The combined organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byCombiFlash (20-40% EtOAc in PE) to give 1-benzyl 3-methyl3-(hydroxymethyl)piperidine-1,3-dicarboxylate (282-1). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.40-7.26 (m, 5H), 5.15 (s, 2H), 4.06-3.80 (m, 1H),3.75-3.60 (m, 6H), 3.50-3.25 (m, 1H), 3.15-2.85 (m, 1H), 1.84-1.71 (m,1H), 1.70-1.62 (m, 1H), 1.61-1.50 (m, 2H). LC-MS: [M+H]⁺=308.0.

To a solution of 1-benzyl 3-methyl3-(hydroxymethyl)piperidine-1,3-dicarboxylate (282-1) (13.4 g, 43.6mmol, 1.0 eq.) in dry DCM (150 mL) was added DMP (36.97 g, 87.21 mmol,2.0 eq.) portion-wise at 0° C. The resulting mixture was stirred at11-20° C. for 2 hours. The mixture was poured into saturated NaHCO₃solution (300 mL) and extracted with DCM (300 mL*3), washed with NaHCO₃aq. (400 mL*2), dried over Na₂SO₄, concentrated. The residue waspurified by flash chromatography (PE/EA=80/20) to give 1-benzyl 3-methyl3-formylpiperidine-1,3-dicarboxylate (282-2). ¹H NMR (400 MHz, CDCl₃) δppm 9.69-9.53 (m, 1H), 7.43-7.28 (m, 5H), 5.14 (s, 2H), 4.42-4.04 (m,1H), 3.86-3.55 (m, 5H), 3.35-3.11 (m, 1H), 2.28-1.90 (m, 2H), 1.73-1.54(m, 2H).

To a solution of 1-benzyl 3-methyl 3-formylpiperidine-1,3-dicarboxylate(282-2) (6.5 g, 21.29 mmol, 1.0 eq.) and comp dimethyl(1-diazo-2-oxopropyl)phosphonateound (8.17 g, 42.58 mmol, 2.0 eq.) indry methanol (120 mL) was added K₂CO₃ (8.8 g, 63.87 mmol, 3.0 eq.). Themixture was stirred at 15-22° C. for 16 hours. The mixture wasconcentrated. The residue was purified by flash chromatography(PE/EA=60/40) to give 1-benzyl 3-methyl3-ethynylpiperidine-1,3-dicarboxylate (282-3). ¹H NMR (400 MHz, CDCl₃) δppm 7.41-7.29 (m, 5H), 5.15 (s, 2H), 4.21-4.07 (m, 1H), 4.00-3.82 (m,1H), 3.75 (s, 3H), 3.54-3.41 (m, 1H), 3.14-2.99 (m, 1H), 2.26-2.17 (m,1H), 2.10-1.82 (m, 3H), 1.92-1.83 (m, 1H), 1.68-1.58 (m, 1H).

To a solution of 1-benzyl 3-methyl 3-ethynylpiperidine-1,3-dicarboxylate(intermediate 282-3) (4 g, 13.27 mmol, 1.0 eq.) in DMF/MeOH (40 mL/4mL), TMSN₃ (2.3 g, 19.91 mmol. 1.5 eq.) was added. The mixture wasstirred at 100-110° C. for 16 hours, diluted with water (100 mL),extracted with EA (100 mL*4), washed with brine (100 mL*3), dried overNa₂SO₄, filtered and concentrated to give crude compound, which waspurified by CombiFlash (DCM/MeOH=10/1) to give 1-benzyl 3-methyl3-(2H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate (Intermediate282-4).LC-MS: [M+H]⁺=345.0.

Intermediate 282-5a: 1-benzyl 3-methyl3-(2-methyl-2H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylateIntermediate 282-5b: 1-benzyl 3-methyl3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate

To a solution of 1-benzyl 3-methyl3-(2H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate (intermediate282-4) (3.3 g, 9.58 mmol, 1.0 eq.) in DMF (40 mL), Cs₂CO₃ (15.6 g, 47.9mmol. 5 eq.) and MeI (9.3 g, 28.74 mmol, 3eq.) were added. The mixturewas stirred at 13-18° C. for 16 hours. The mixture was filtered and thefiltrate was concentrated to give crude compound, which was purified bypre-HPLC to give 1-benzyl 3-methyl3-(2-methyl-2H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate(Intermediate 282-5a) and 1-benzyl 3-methyl3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1,3-dicarboxylate(Intermediate 282-5b).

Intermediate 282-5a: ¹H NMR (400 MHz, CD₃OD) δ ppm 7.63-7.47 (m, 1H),7.44-7.27 (m, 5H), 5.15-5.07 (m, 2H), 4.40-4.15 (m, 1H), 4.09 (s, 3H),3.90-3.70 (m, 1H), 3.60 (brs, 4H), 3.48-3.32 (m, 1H), 2.38 (brs, 1H),2.26-2.10 (m, 1H), 1.70-1.55 (m, 2H). LC-MS: [M+H]⁺=359.3.

Intermediate 282-5b: ¹H NMR (400 MHz, CD₃OD) δ ppm 7.81 (s, 1H),7.44-7.27 (m, 5H), 5.12 (s, 2H), 4.48-4.04 (m, 1H), 4.00 (s, 3H),3.94-3.82 (m, 0.6H), 3.73-3.43 (m, 2H), 3.60 (s, 3H), 3.28-3.17 (m,0.4H), 2.48-2.10 (m, 2H), 1.82-1.47 (m, 2H).

Intermediate 282-6:1-((Benzyloxy)carbonyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-3-carboxylicacid

Intermediate 282-6 was prepared by using a procedure similar to that ofintermediate 281-6 in Example 281 by replacing intermediate 281-5 withintermediate 282-5a. LC-MS: [M+H]⁺=345.4.

Intermediate 282-7: Benzyl3-carbamoyl-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

Intermediate 282-7 was prepared by using a procedure similar to that ofintermediate 281-7 in Example 281 by replacing intermediate 281-6 withintermediate 282-6. LC-MS: [M+H]⁺=344.1.

Intermediate 282-8: Benzyl3-((methoxycarbonyl)amino)-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

Intermediate 282-8 was prepared by using a procedure similar to that ofintermediate 177-3 in Example 177 by replacing intermediate 177-3 withintermediate 281-7. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.64-7.30 (m, 6H),5.29-5.10 (m, 2H), 4.09-3.71 (m, 6H), 3.57 (s, 3H), 3.30 (brs, 1H),2.69-2.45 (m, 1H), 2.37-2.15 (m, 1H), 1.82-1.65 (m, 1H), 1.55-1.45 (m,1H). LC-MS: [M+H]⁺=374.1.

Intermediate 282-9: Methyl(3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-3-yl)carbamate

Intermediate 282-9 was prepared by using a procedure similar to that ofintermediate 269-4 in Example 269 by replacing intermediate 269-3 withintermediate 281-8. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.81 (s, 1H), 4.06 (s,3H), 3.56 (s, 3H), 3.40-3.32 (m, 1H), 3.13-2.89 (m, 2H), 2.71-2.62 (m,1H), 2.39 (d, J=13.6 Hz, 1H), 2.08-1.99 (m, 1H), 1.79-1.66 (m, 1H),1.57-1.47 (m, 1H).

Intermediate 282-10: Methyl2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)isonicotinate

Intermediate 282-10 was prepared by using a procedure similar to that ofintermediate 177-5 in example 177 by replacing intermediate 177-4 withintermediate 282-9. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (s, 1H), 7.98 (s,1H), 7.87-7.81 (m, 12 Hz, 1H), 7.72-7.67 (m, 1H), 7.64 (s, 1H),7.27-7.20 (m, 1H), 6.87 (brs, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.72-3.68(m, 0.5H), 3.66 (s, 3H), 3.60-3.50 (m, 0.5H), 3.35 (d, J=11.2 Hz, 1H),3.18 (d, J=12.4 Hz, 1H), 3.10 (td, J=11.6 Hz, 2.8 Hz, 1H), 2.94 (d,J=11.2 Hz, 1H), 2.09-1.70 (m, 3H). LC-MS: [M+H]⁺=487.5.

Intermediate 282-11: methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-3-yl)carbamate

Intermediate 282-11 was prepared by using a procedure similar to that ofintermediate 177-6 in example 177 by replacing intermediate 177-5 withintermediate 282-10. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.46 (s, 1H),7.86-7.80 (m, 1H), 7.70-7.66 (m, 1H), 7.65 (s, 1H), 7.57 (s, 1H),7.25-7.19 (m, 1H), 5.75 (brs, 1H), 4.85-4.77 (m, 2H), 4.08 (s, 3H), 3.95(brs, 1H), 3.62 (s, 3H), 3.69-3.52 (m, 1H), 3.42 (d, J=11.2 Hz, 1H),3.13 (d, J=11.6 Hz, 1H), 3.03-2.94 (m, 1H), 2.64-2.52 (m, 1H), 2.25-2.10(m, 1H), 2.02-1.94 (m, 1H), 1.85-1.77 (m, 1H). LC-MS: [M+H]⁺=459.1.

Intermediate 282-12: tert-Butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

Intermediate 282-12 was prepared by using a procedure similar to that ofintermediate 177-7 in example 177 by replacing intermediate 177-6 withintermediate 282-11. LC-MS: [M+H]⁺=776.3.

Intermediate:284-4: 3-(5-methylisoxazol-3-yl)piperidin-3-amine

A mixture of benzyl3-((tert-butoxycarbonyl)amino)-3-formylpiperidine-1-carboxylate (238 mg,0.656 mmol) and hydroxylamine HCl (38 mg, 0.547 mmol) and K₂CO₃ (91 mg,0.656 mmol) in EtOH/H₂O (1:1, 20 mL) was stirred at rt overnight, andthe mixture was treated with EA (20 mL) and H₂O (10 mL). The layers wereseparated and the aqueous layers were extracted with EA (10 mL*2). Thecombined organic layer were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated to give benzyl(E)-3-((tert-butoxycarbonyl)amino)-3-((hydroxyimino)methyl)piperidine-1-carboxylate(284-1). LC-MS: [M+H−100]⁺=277.9.

A mixture of benzyl(E)-3-((tert-butoxycarbonyl)amino)-3-((hydroxyimino)methyl)piperidine-1-carboxylate(284-1) (2 g, 5.3 mmol) in DMF (20 mL) was added NCS (1.061 g, 7.95mmol). The mixture was stirred at 40° C. for 2 hrs. Then the mixture wastreated with EA (20 mL) and H₂O (20 mL). The layers were separated andthe aqueous layers were extracted with EA (20 mL*2). The combinedorganic layer were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated to give crude benzyl(Z)-3-((tert-butoxycarbonyl)amino)-3-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (284-2).

To a mixture of crude benzyl(Z)-3-((tert-butoxycarbonyl)amino)-3-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (284-2) (2 g, 4.86 mmol) in DCM (50 mL)was added 2-chloroprop-1-ene (7.43 g, 97 mmol) and TEA (3.41 mL, 24.28mmol). The mixture was heated to 40° C. for overnight. Then the mixturewas concentrated. The residue was purified, eluting with EA in n-hexane(0 to 50%) to give benzyl3-((tert-butoxycarbonyl)amino)-3-(5-methylisoxazol-3-yl)piperidine-1-carboxylate(284-3). LC-MS: [M+H]⁺=415.9.

A mixture of benzyl3-((tert-butoxycarbonyl)amino)-3-(5-methylisoxazol-3-yl)piperidine-1-carboxylate(284-3) (700 mg, 1.685 mmol) in HBr in HOAc (10 mL) was stirred at rtfor 8 hrs. The mixture was concentrated and the residue was adjustedpH=10-12 with 1 M of aq. NaOH. The mixture was then extracted withi-PrOH/DCM (1:3 20 mL*3). The combined organic layers were dried overNa₂SO₄ and filtered. The filtrate was concentrated to3-(5-methylisoxazol-3-yl)piperidin-3-amine (Intermediate 284-4). LC-MS:[M+H]⁺=182.0.

Intermediate 284-6:(5-(3-amino-3-(5-methylisoxazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methanol

Methyl5-(3-amino-3-(5-methylisoxazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(Intermediate 284-5) was prepared following procedures analogous tothose described in Example 177-5 and from corresponding intermediates.LC-MS: [M+H]⁺=428.9, 429.8.

Intermediate 284-6 was prepared by using a procedure similar to that ofintermediate 177-6 in example 177 by replacing intermediate 177-5 withintermediate 284-5. LC-MS: [M+H]⁺=400.9, 401.9.

Intermediate 285-4: 3-(2-(benzyloxy)-1-fluoroethyl)piperidin-3-amine

To a solution of 2-(benzyloxy)acetaldehyde (0.652 g, 4.34 mmol) in 0.025M NaOH aqueous solution (15 mL, 0.375 mmol) was added2-(benzyloxy)acetaldehyde (0.652 g, 4.34 mmol) andN,N,N-trimethylhexadecan-1-aminium chloride (0.139 g, 0.434 mmol) at rt,the mixture was stirred at rt for 3 h under N₂ atmosphere. The reactionmixture was diluted with water, extracted with EtOAc (20 ml*3), thecombined organic phase was washed with water (20 ml), brine (20 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to give aresidue. The residue was purified by flash chromatography (elutiongradient: 0% to 30% EtOAc in PE in 30 mins) to afford the tert-butyl3-(2-(benzyloxy)-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate(285-1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm. 40-7.24 (m, 6H), 5.84 (dd,J=28.5, 6.2 Hz, 1H), 4.79-4.56 (m, 1H), 4.54-4.44 (m, 2H), 4.07-3.91 (m,1H), 3.85 (s, 1H), 3.59 (ddd, J=27.8, 10.5, 4.9 Hz, 1H), 3.39 (ddd,J=12.0, 10.4, 6.3 Hz, 1H), 3.18 (dd, J=22.8, 13.2 Hz, 1H), 2.72 (s, 1H),2.41 (t, J=15.6 Hz, 1H), 1.95-1.77 (m, 1H), 1.61 (dt, J=14.0, 3.9 Hz,1H), 1.37 (d, J=2.5 Hz, 9H). LC-MS: [M+H−100]⁺=281.2.

To a solution of tert-butyl3-(2-(benzyloxy)-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate (285-1)(0.93 g, 2.445 mmol) in DCM (20 mL), was added DAST (0.646 mL, 4.89mmol) at 0° C., the mixture was stirred at 0° C. for 3 h under N₂atmosphere. Then the reaction mixture was diluted with water, extractedwith EtOAc (20 ml*3), and worked up in aqueous conditions to give aresidue when concentrated in vacuum. The residue was purified by flashchromatography (elution gradient: 0% to 40% EtOAc in PE in 30 mins) toafford tert-butyl3-(2-(benzyloxy)-1-fluoroethyl)-3-nitropiperidine-1-carboxylate (285-2).LC-MS: [M+H−100]+=383.1.

To a solution of tert-butyl3-(2-(benzyloxy)-1-fluoroethyl)-3-nitropiperidine-1-carboxylate (285-2)(200 mg, 0.684 mmol) in EtOH (10 mL), was added Zn dust (44.7 mg, 0.684mmol) at RT, then 4M HCl (2.281 mL, 6.84 mmol) was added dropwise at 0°C., after addition the mixture was stirred at 0° C. for 3 h under N₂atmosphere. The reaction mixture was filtered and concentrated to give aresidue. The residue was purified by flash chromatography (elutiongradient: 0% to 40% EtOAc in PE in 30 mins) to afford tert-butyl3-amino-3-(2-(benzyloxy)-1-fluoroethyl)piperidine-1-carboxylate (285-3).LC-MS: [M+H]⁺=263.2.

To a solution of tert-butyl3-amino-3-(2-(benzyloxy)-1-fluoroethyl)piperidine-1-carboxylate (285-3)(180 mg, 0.511 mmol) in DCM (15 mL), was added TFA (5 mL, 64.9 mmol) atrt, the mixture was stirred at rt for 1 h under N₂ atmosphere. Then themixture was concentrated in vacuum to afford3-(2-(benzyloxy)-1-fluoroethyl)piperidin-3-amine (Intermediate 285-4) asTFA salt. LC-MS: [M+H]⁺=253.2.

Intermediate 287-6: 2,2,2-trifluoroacetaldehyde Compound withN-benzyl-3-(1,2-difluoroethyl)piperidin-3-amine (1:1)

AlLiH₄ (13.42 g, 353.45 mmol) in THF (200 mL) was stirred at 80° C. for2 h. Then the mixture was added to ethyl 2-fluoroacetate (150 g, 1.41mol) in THF (100 mL) at −60° C. and stirred at −60° C. for 1 h. Themixture was quenched by EtOH (20 mL) at −60° C., poured into a solutionof ice-water (500 mL) and H₂SO₄ (50 mL), and extracted with MTBE (150mL*3). The organic layers were concentrated in vacuo (25° C.) to giveresidue. The residue was purified by distillation (−0.095 MPa, 25-50°C.) to give 1-ethoxy-2-fluoroethan-1-ol (287-1). ¹H NMR (400 MHz, CD₃OD)δ=4.30-4.16 (m, 2H), 3.61 (q, J=7.1 Hz, 2H), 1.20-1.18 (m, 3H).

To a solution of tert-butyl 3-nitropiperidine-1-carboxylate (40 g,173.72 mmol) in THF (40 mL) was added 1-ethoxy-2-fluoroethan-1-ol(287-1) (93.90 g, 868.58 mmol), K₂CO₃ (12.00 g, 86.86 mmol) and stirredat 40° C. for 4 h. The mixture was concentrated in vacuo to give aresidue. The residue was purified by column chromatography(PE/EA=50:1-10:1) to give tert-butyl3-(2-fluoro-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate (287-2). ¹HNMR (400 MHz, CDCl₃) 5=4.78-4.62 (m, 1H), 4.60-4.50 (m, 1H), 4.50-4.41(m, 1H), 4.22-4.02 (m, 1H), 3.99-3.60 (m, 1H), 3.48-2.92 (m, 2H),2.57-2.37 (m, 1H), 2.34-2.10 (m, 1H), 1.74-1.64 (m, 2H), 1.47 (m, 9H).LCMS: [M+H−56]⁺=237.3.

To a solution of tert-butyl3-(2-fluoro-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate (287-2) (25g, 85.53 mmol) in DCM (100 mL) was added BAST (85.15 g, 384.87 mmol) andstirred at 50° C. for 4 h. The mixture was quenched with aq.NaHCO₃ (1.0L), extracted with EA (200 mL*3). The organic layer was concentrated invacuo to give a residue. The residue was purified by columnchromatography (PE:EA=100:1-20:1) to give tert-butyl3-(1,2-difluoroethyl)-3-nitropiperidine-1-carboxylate (287-3). LCMS:[M+H−56]⁺=239.3.

To a solution of tert-butyl3-(1,2-difluoroethyl)-3-nitropiperidine-1-carboxylate (287-3) (10.0 g,33.98 mmol) in MeOH (100 mL) was added Pd/C (5.0 g, 10% purity) andstirred under H₂ (15 Psi) at 40° C. for 16 h. The mixture was filteredand concentrated in vacuo to give crude tert-butyl3-amino-3-(1,2-difluoroethyl)piperidine-1-carboxylate (287-4). LCMS:[M+H−56]⁺=209.3.

To a solution oftert-butyl3-amino-3-(1,2-difluoroethyl)piperidine-1-carboxylate (287-4) (8.1 g,30.65 mmol) and benzaldehyde (4.88 g, 45.97 mmol) in EtOH (100 mL) wasstirred at 40° C. for 1 h.Then NaBH₄ (5.8 g, 153.23 mmol) was added tothe mixture and stirred at 40° C. for 16 h. LCMS detected the reaction.The mixture was quenched by aq.NH₄Cl (100 mL), diluted with H₂O (200mL), extracted with EA (50 mL*3). The organic layer was concentrated invacuo to give tert-butyl3-(benzylamino)-3-(1,2-difluoroethyl)piperidine-1-carboxylate (287-5).LCMS: [M+H]⁺=355.4.

To a solution of tert-butyl3-(benzylamino)-3-(1,2-difluoroethyl)piperidine-1-carboxylate (287-5)(7.0 g, 19.75 mmol) in DCM (20 mL) was added TFA (10 mL) and stirred at40° C. for 3 h. The mixture was quenched by aq.NaHCO₃ (200 mL),extracted with DCM (50 mL*3). The organic layer was concentrated invacuo to give 2,2,2-trifluoroacetaldehyde compound withN-benzyl-3-(1,2-difluoroethyl)piperidin-3-amine (1:1) (Intermediate287-6). LCMS: [M+H]⁺=254.9.

To a stirred solution of NaH (7.7 g, 180 mmol, 1.0 eq) in anhydrous THF(120 ml) at 0° C. was added prop-2-en-1-ol (10.4 g, 180 mmol, 1.0 eq)dropwise. The reaction mixture was stirred for 15 min at 0° C., andstirred at 15° C. for another 15 min. Besides, to another suspension ofNaH (7.7 g, 180 mmol, 1.0 eq) and THF (60 mL) was added 2-chloroaceticacid in anhydrous at 0° C., after stirred at 0° C. for 15 mins, thepreviously prepared solution was added and the reaction mixture wasstirred at 15° C. for 12 hours. The reaction mixture was quenched bywater (100 mL), the aqueous layer was acidified and extracted with EA(200 mL*3), dried over anhydrous Na₂SO₄, filtered and concentrated togive 2-(allyloxy)acetic acid (288-1). ¹H NMR (400 MHz, CDCl3) δ ppm5.98-5.85 (m, 1H), 5.39-5.22 (m, 2H), 4.15 (s, 2H), 4.13 (m, 2H). LC-MS:[M+Na]+=161.1.

To a solution of 2-(allyloxy)acetic acid (288-1) (9.2 g, 79.23 mmol, 1.0eq) in anhydrous DCM (60 mL) was added DMF (115 mg, 1.58 mmol, 0.02 eq)and (COCI)₂ (12.1 g, 95.07 mmol, 1.2 eq) dropwise at 15° C. The reactionmixture was stirred at 15° C. for 2 hours. The reaction mixture wasconcentrated in vacuum to give crude 2-(allyloxy)acetyl chloride(288-2). LC-MS: [M+C₇H₉N—HCl+H]+=206.2.

To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (16.9 g,60.94 mmol, 1.0 eq) in anhydrous THF (170 mL) was added a solution ofLiHMDS (61 mL, 60.94 mmol, 1.0 eq) dropwise at −78° C. The reactionmixture was stirred at −78° C. for 1 hour, 2-(allyloxy)acetyl chloride(288-2) (8.2 g, 60.94 mmol, 1.0 eq) was added dropwise at −78° C., thereaction was stirred at −78° C. for 1 hour and at 15° C. for another 1hour. The reaction mixture was quenched with sat. NH₄Cl (200 mL),extracted with EA (100 mL*3), dried over Na₂SO₄, filtered, andconcentrated to give crude 1-benzyl 3-methyl3-(2-(allyloxy)acetyl)piperidine-1,3-dicarboxylate (288-3). LC-MS:[M+H]⁺=376.2.

To a solution of 1-benzyl 3-methyl3-(2-(allyloxy)acetyl)piperidine-1,3-dicarboxylate (288-3) (20.4 g,53.34 mmol, 1.0 eq) in MeOH (100 mL) was added NaBH₄ (2.0 g, 53.34 mmol,1.0 eq) portionwise at 15° C. The reaction was stirred at 15° C. for 3hours. The reaction mixture was quenched with Sat. NH₄Cl (100 mL),acidified with 2N HCl to PH=4-5, extracted with EtOAc (100 ml*3), thecombined organic phase was washed with water (100 ml), brine (100 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to give aresidue. The residue was purified by column chromatography (SiO₂,PE/EA=20:1 to 1:1) to give 1-benzyl 3-methyl3-(2-(allyloxy)-1-hydroxyethyl)piperidine-1,3-dicarboxylate (288-4).LC-MS: [M+H]⁺=378.3.

To a solution of 1-benzyl 3-methyl3-(2-(allyloxy)-1-hydroxyethyl)piperidine-1,3-dicarboxylate (288-4)(10.4 g, 27.55 mmol, 1.0 eq) in dry MeCN (100 mL) was added NIS (10.6 g,4.684 mmol, 1.7 eq). The reaction mixture was stirred at 90° C. for 3hours. The reaction mixture was quenched with Sat. Na₂SO₃ (50 mL),extracted with EA (100 mL*3), dried over anhydrous Na₂SO₄, concentrated.The residue was purified by column chromatography (SiO₂, PE/EA=20/1 to2/1) to give 1-benzyl 3-methyl3-(6-(iodomethyl)-1,4-dioxan-2-yl)piperidine-1,3-dicarboxylate (288-5).LC-MS: [M+H]⁺=504.2.

To a solution of 1-benzyl 3-methyl3-(6-(iodomethyl)-1,4-dioxan-2-yl)piperidine-1,3-dicarboxylate (288-5)(4.3 g, 8.54 mmol, 1.0 eq) and n-Bu₃SnH (2.5 g, 8.54 mmol, 1.0 eq) andin anhydrous toluene (200 mL) was added AIBN (140 mg, 0.85 mmol, 0.1eq), the reaction mixture was stirred under N₂ for 16 hours. Thereaction mixture was quenched by a solution of KF (0.5 g, 8.54 mmol, 1.0eq) in H₂O (50 mL), diluted with water (100 mL), extracted with EA (100mL*3), dried over anhydrous Na₂SO₄, concentrated in vacuo to giveresidue. The residue was purified by column chromatography (SiO₂,PE/EA=20/1 to 1/1) to give 1-benzyl 3-methyl3-(6-methyl-1,4-dioxan-2-yl)piperidine-1,3-dicarboxylate (288-6). LC-MS:[M+H]⁺=378.3.

To a solution of 1-benzyl 3-methyl3-(6-methyl-1,4-dioxan-2-yl)piperidine-1,3-dicarboxylate (288-6) (3.6 g,9.54 mmol, 1.0 eq) in MeOH (50 mL) was added a solution of LiOH.H₂O (4.0g, 95.38 mmol, 10.0 eq) in H₂O (50 mL) at RT. The reaction was stirredat RT for 16 hours. The reaction mixture was concentrated in vacuum toremove most of MeOH, diluted with 20 ml of water, the aqueous phase waswashed with EA (10 mL*3). Then the aqueous phase was acidified with 2NHCl to PH=3-4, extracted with EA (50 mL*3), dried over anhydrous Na₂SO₄,concentrated in vacuo to give1-((benzyloxy)carbonyl)-3-(6-methyl-1,4-dioxan-2-yl)piperidine-3-carboxylicacid (288-7). LC-MS: [M+H]⁺=364.3.

To a solution of1-((benzyloxy)carbonyl)-3-(6-methyl-1,4-dioxan-2-yl)piperidine-3-carboxylicacid (288-7) (2.1 g, 5.78 mmol, 1.0 eq) in anhydrous THF (800 mL) wasadded TEA (1.7 g, 17.34 mmol, 3.0 eq) and DPPA (2.2 g, 8.09 mmol, 1.4eq) at 20° C., the reaction mixture was stirred at 70° C. for 2 hoursand cooled to 20° C. then a solution of KOH (1.0 g, 17.34 mmol, 3.0 eq)in H₂O (10 mL) was added. The reaction mixture was stirred at 20° C. for2 hours. The reaction mixture was concentrated, extracted with EA (50mL*3), washed with water (50 mL), brine (50 mL). The organic layer wasdried over Na₂SO₄, concentrated in vacuo. The crude was purified bycolumn chromatography (SiO₂, PE/EA=20/1 to EA) to give a not pureproduct, which was further purified by Prep-HPLC to give benzyl3-amino-3-(6-methyl-1,4-dioxan-2-yl)piperidine-1-carboxylate (288-8). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.39-7.21 (m, 5H), 5.06 (m, 2H), 3.96-2.86(m, 10H), 1.82-1.61 (m, 2H), 1.52-1.31 (m, 2H), 1.30-0.96 (m, 3H).LC-MS: [M+H]⁺=335.3.

To a solution of benzyl3-amino-3-(6-methyl-1,4-dioxan-2-yl)piperidine-1-carboxylate (288-8)(1.0 g, 2.99 mmol, 1.0 eq) in MeOH (10 ml) was added Pd(OH)₂ (104 mg,10% wt), the reaction mixture was stirred at 20° C. under H₂ atmosphere(16 Psi) for 8 hours. The reaction mixture was filtered and concentratedin vacuum to give crude 3-(6-methyl-1,4-dioxan-2-yl)piperidin-3-amine(Intermediate 288-9).

Intermediate 292-3: 3-oxa-1,7-diazaspiro[4.5]decan-2-one

To a solution of 1-benzyl 3-ethyl3-(hydroxymethyl)piperidine-1,3-dicarboxylate (intermediate 22-2) (2.0g, 6.97 mmol, 1.0 eq.) in THF/MeOH/H₂O (1:1:1, 30 mL) was added LiOH H₂O(0.87 g, 20.9 mmol, 3.0 eq.) at 20° C. The mixture was stirred at 20° C.for 8 h. Water (50 mL) was added and the mixture was extracted withEtOAc (100 mL*3). The aqueous phase was acidified by 1M HCl to pH=2-3and then extracted with EtOAc (100 mL*3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated to give1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carboxylic acid(292-1). H NMR (CDCl₃ 400 MHz): δ 4.05-3.85 (m, 1H), 3.85-3.65 (m, 3H),3.45-3.20 (m, 1H), 3.14-2.95 (m, 1H), 1.97-1.85 (m, 1H), 1.80-1.70 (m,1H), 1.62-1.52 (m, 2H), 1.44 (s, 9H).

To a solution of1-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine-3-carboxylic acid(292-1) (1.8 g, 6.94 mmol, 1.0 eq.) in toluene (40 mL) was added TEA(1.4 g, 13.9 mmol, 2.0 eq.) and DPPA (2.7 g, 10.4 mmol, 1.5 eq.) underN₂ at 20° C. Then the reaction mixture was stirred at 110° C. for 8 h.H₂O (100 mL) was added and the mixture was extracted with EtOAc (100mL*3). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography (PE:EA=1:1) to givetert-butyl 2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate (292-2).¹H NMR (CDCl₃ 400 MHz): δ 5.87 (brs, 1H), 4.22 (d, J=8.8 Hz, 1H), 4.07(d, J=8.8 Hz, 1H), 3.66-3.42 (m, 2H), 3.38-3.18 (m, 2H), 1.85-1.78 (m,2H), 1.75-1.65 (m, 1H), 1.60-1.52 (m, 1H), 1.48 (s, 9H).

A solution of tert-butyl2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate (292-2) (0.6 g, 2.34mmol, 1.0 eq.) in HCl/dioxane (5 mL, 4N) was stirred at 20° C. for 2 h.The mixture was concentrated to give crude3-oxa-1,7-diazaspiro[4.5]decan-2-one (Intermediate 292-3).

Intermediate 293-8: 3-(1,1-difluoroprop-1-en-2-yl)piperidin-3-amine

To a solution of tert-butyl 3-cyanopiperidine-1-carboxylate (25 g, 119.0mmol, 1.0 eq.) in THF (300 mL) at −70° C. under N₂ atmosphere was addedLiHMDS (178 mL, 178.57 mmol, 1.5 eq.) dropwise. The reaction mixture wasstirred at −70° C. for 30 min, then CH₃CHO (7.85 g, 178.57 mmol, 3 eq.)was added. The reaction was quenched with aq.NH₄Cl (200 mL), extractedwith EtOAc (100 mL×3). The combined organic layer was washed with brine(200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by Combi-flash (EtOAc in PE,10%-50%) to afford tert-butyl3-(1-hydroxyethyl)-3-methylpiperidine-1-carboxylate (293-1).

To a solution of tert-butyl3-(1-hydroxyethyl)-3-methylpiperidine-1-carboxylate (intermediate 293-1)(9 g, 35.43 mmol, 1.0 eq.) in DCM (150 mL) was added DMP (22.5 g, 53.15mmol, 1.5 eq.). The mixture was stirred at 20° C. for 1 hour. Thereaction was quenched with aq. NaHCO₃ (150 mL) and aq. Na₂SO₃ (150 mL),extracted with EtOAc (150 mL×3). The combined organic layers were washedwith aq.NaHCO₃ (150 mL), dried over anhydrous sodium sulfate, filteredand concentrated to afford tert-butyl3-acetyl-3-cyanopiperidine-1-carboxylate (293-2). ¹H NMR (400 MHz,CDCl₃) δ ppm 4.50-3.85 (m, 2H), 3.20-3.05 (m, 1H), 2.95-2.60 (m, 1H),2.46 (s, 3H), 2.25-1.70 (m, 4H), 1.48 (s, 9H).

To a solution of tert-butyl 3-acetyl-3-cyanopiperidine-1-carboxylate(293-2) (5 g, 19.84 mmol, 1.0 eq.) in DCM (100 mL) was added TFA (15mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixturewas then concentrated. The residue was diluted with EtOAc (150 mL), andaq.NaHCO₃ (150 mL) was added. Then CbzCl (4.0 g, 23.81 mmol, 1.2 eq) wasadded. The reaction mixture was stirred at 20° C. for another 1 h. Theproduct was extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by combi-flash (EtOAc in PE,0%-30%) to afford benzyl 3-acetyl-3-cyanopiperidine-1-carboxylate(293-3). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.45-7.30 (m, 5H), 5.25-5.10 (m,2H), 4.50-4.05 (m, 2H), 3.20 (d, J=13.6 MHz, 1H), 2.95-2.75 (m, 1H),2.47 (d, J=16.8 MHz, 3H), 2.25-1.60 (m, 4H).

To a solution of benzyl 3-acetyl-3-cyanopiperidine-1-carboxylate (293-3)(5 g, 17.46 mmol, 1.0 eq.) and 2-((difluoromethyl)sulfonyl)pyridine (5g, 26.19 mmol, 1.5 eq.) in THF (50 mL) was added KHMDS (26 mL, 26.19mmol, 1.5 eq.) dropwise at −70° C. under N₂ atmosphere. The mixture wasstirred at −70° C. for 2 hours. The reaction was quenched with aq. NH₄Cl(50 mL) and extracted with EtOAc (50 mL×3). The organic layers werewashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to afford benzyl3-cyano-3-(1,1-difluoro-2-hydroxy-1-(pyridin-2-ylsulfonyl)propan-2-yl)piperidine-1-carboxylate(293-4). LC-MS: [M+H]⁺=480.0.

To a solution of benzyl3-cyano-3-(1,1-difluoro-2-hydroxy-1-(pyridin-2-ylsulfonyl)propan-2-yl)piperidine-1-carboxylate(293-4) (12 g, crude) in DMF (30 mL) was added sat. NH₄Cl (30 mL) andaq. HCl (30 mL, 6M). The reaction mixture was stirred at 80° C. for 48hours. The reaction was cooled and diluted with H₂O (50 mL). The productwas extracted with EtOAc (50 mL×3). The organic layers were washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by combi-flash (EtOAc in PE, 0%-20%) to affordbenzyl 3-cyano-3-(1,1-difluoroprop-1-en-2-yl)piperidine-1-carboxylate(293-5). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.45-7.30 (m, 5H), 5.30-5.15 (m,2H), 4.65-4.15 (m, 2H), 3.10-2.70 (m, 2H), 2.25 (d, J=11.2 MHz, 1H),2.10-1.60 (m, 6H). LC-MS: [M+H]⁺=320.9.

To a mixture of benzyl3-cyano-3-(1,1-difluoroprop-1-en-2-yl)piperidine-1-carboxylate (293-5)(2.7 g, 8.44 mmol, 1.0 eq), 1 M NaOH solution (12.6 mL, 1.5 eq) in MeOH(100 mL) was added H₂O₂ (30%, 6.68 g, 59 mmol, 7.0 eq). The reaction wasstirred at 18° C. for 36 hrs. The reaction was quenched with saturatedNa₂S₂O₃ (50 mL). The aqueous layer was extracted with EtOAc (50 mL×3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated into dryness. The residue was purified by combi-flash(EtOAc in PE, 0-40%) to afford benzyl3-carbamoyl-3-(1,1-difluoroprop-1-en-2-yl)piperidine-1-carboxylate(293-6). ¹H NMR (CDCl₃ 400 MHz): δ ppm 7.42-7.30 (m, 5H), 5.22-5.08 (m,2H), 4.48 (brs, 1H), 3.99 (brs, 1H), 3.17-2.88 (m, 2H), 2.53 (brs, 1H),1.76-1.46 (m, 7H).

To a solution of benzyl3-carbamoyl-3-(1,1-difluoroprop-1-en-2-yl)piperidine-1-carboxylate(293-6) (1.34 g, 4 mmol, 1.0 eq) and KOH (560 mg, 10 mmol, 2.5 eq) inMeOH (30 mL) was added PhI(OAc)₂ (1.53 g, 4.8 mmol, 1.2 eq) at 0° C. Theresulting mixture was stirred at 15° C. for 3 hr. The reaction wasquenched with sat. NH₄Cl solution (50 mL). The aqueous layer wasextracted with EtOAc (50 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified bycombi-flash (EtOAc in PE, 0-30%) to afford benzyl3-(1,1-difluoroprop-1-en-2-yl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(293-7). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.42-7.30 (m, 5H), 5.24-5.08 (m,2H), 4.30 (d, J=14.2 Hz, 1H), 4.18-4.04 (m, 1H), 3.60 (s, 3H), 2.82(brs, 2H), 1.73-1.60 (m, 4H), 1.57 (s, 3H). LC-MS: [M+H]⁺=369.0.

To a solution of benzyl3-(1,1-difluoroprop-1-en-2-yl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(293-7) (600 mg, 1.63 mmol, 1.0 eq) in DCM (15 mL) was added TMSI (977mg, 4.89 mmol, 3.0 eq). The reaction was stirred at 16° C. for 18 hr.The reaction was quenched with water (10 mL). The aqueous layer wasadjusted to pH=4-5 by 1 M HCl solution. The mixture was partitionedbetween DCM and water. The aqueous layer was lyophilized to afford3-(1,1-difluoroprop-1-en-2-yl)piperidin-3-amine HCl salt (Intermediate293-8). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.73 (d, J=13.4 Hz, 1H), 3.17(d, J=12.8 Hz, 2H), 2.98 (t, J=10.2 Hz, 1H), 2.27 (d, J=13.6 Hz, 1H),2.01-1.78 (m, 2H), 1.71 (t, J=3.4 Hz, 3H), 1.65-1.50 (m, 1H). LC-MS:[M+H]⁺=177.1

Intermediate 295-6: 3-(1-fluoroethyl)piperidin-3-amine

To solution of 1-benzyl 3-methyl3-((tert-butoxycarbonyl)amino)piperidine-1,3-dicarboxylate (160 mg, 0.41mmol) in MeOH (10 ml) was added LiCl (510 mg, 12.3 mmol) and NaBH₄ (462mg, 12.3 mmol) at room temerature. The reaction mixture was stirred atthis temperature until no starting material left. The reaction mixturewas diluted with EA, washed with 1 N HCl and brine. The organic layerwas dried over Na₂SO₄ and concentrated under vacuum to give the crudealcohol. LC-MS: [M+H−100]⁺=265.0.

To a solution of the alcohol (560 mg, 1.537 mmol) in DCM (15 ml) wasadded Dess-Martin reagent (782 mg, 1.844 mmol). The mixture was stirredat rt for 2 hrs. The mixture was treated with aq. NaHCO₃ (10 ml) and thelayers were separated. The aqueous layer was extracted with DCM (10ml*2). The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated. The residue waspurified, eluting with EA in n-hexane (0 to 50%) to give benzyl3-((tert-butoxycarbonyl)amino)-3-formylpiperidine-1-carboxylate (295-1).LC-MS: [M+H−100]⁺=624.8.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-formylpiperidine-1-carboxylate (295-1)(100 mg, 0.276 mmol) in THF (10 ml) was added dropwise aq. CH₃MgBr in2-Me THF (3M, 0.138 ml, 0.414 mmol) at −78° C. The mixture was stirredat −78° C. for another 1 hr and was allowed to warm to 0° C. for another2 hr. The mixture was quenched with aq. NH₄Cl (10 ml) and was extractedwith EA (20 ml*3). The combined organic layers were washed with brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated. Theresidue was purified, eluting with EA in n-hexane (0 to 50%) to give thealcohol. LC-MS: [M+H−100]⁺=279.0. To a solution of the alcohol (100 mg,0.264 mmol) in DCM (3 ml) was added TFA (0.5 ml). The resulting mixturewas stirred at rt for 2 hrs. The mixture was concentrated under vacuum(below 40° C.) to give benzyl3-amino-3-(1-hydroxyethyl)piperidine-1-carboxylate (295-2). LC-MS[M+H]⁺=279.0.

To a solution of benzyl3-amino-3-(1-hydroxyethyl)piperidine-1-carboxylate (295-2) (330 mg,1.186 mmol), DMAP (14.48 mg, 0.119 mmol) and DIPEA (0.958 mL, 5.34 mmol)in DCM (20 mL) was added NsCl (657 mg, 2.96 mmol) in portions. Themixture was stirred at rt under N₂ overnight. The reaction was treatedwith aq. NaHCO₃ (20 mL). The layers were separated. The aqueous layerwas extracted with DCM (20 mL*2). The combined organic layers werewashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated. The residue was purifed, eluting with n-hexane in EA (0 to30%) to give benzyl2-methyl-1-((4-nitrophenyl)sulfonyl)-1,5-diazaspiro[2.5]octane-5-carboxylate(295-3). LC-MS: [M+H]⁺=445.8.

To a solution of benzyl2-methyl-1-((4-nitrophenyl)sulfonyl)-1,5-diazaspiro[2.5]octane-5-carboxylate(295-3) (420 mg, 0.943 mmol) in THF (10 mL) was added 1 M TBAF in THF(0.606 ml, 0.606 mmol) under N₂. The mixture was heated to 45° C.overnight. The mixture was cooled to rt and was treated with EA (15 mL)and H₂O (10 mL). The layers were separated and the aqueous layer wasextrtacted with EA (15 mL*3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated and was purified via prep. HPLC to give benzyl3-(1-fluoroethyl)-3-((4-nitrophenyl)sulfonamido)piperidine-1-carboxylate(295-4). LC-MS: [M+H]⁺=465.8.

A mixture of thioglycolic acid (71.2 mg, 0.773 mmol) and DBU 235 (98 mg,1.547 mmol) in CH₃CN (10 mL) was stirred under N₂ for 5 min. Then benzyl3-(1-fluoroethyl)-3-((4-nitrophenyl)sulfonamido)piperidine-1-carboxylate(295-4) (120 mg, 0.258 mmol) in CH₃CN (2 mL) was added. The mixture wasstirred at rt overnight and concentrated. The residue was treated withEA (10 ml) and was washed with aq. NaHCO₃ (5 mL*2), H₂O (10 mL) andbrine, dried over Na₂SO₄ and filtered. The filtrate was concentrated andthe residue purified via prep. HPLC to give benzyl3-amino-3-(1-fluoroethyl)piperidine-1-carboxylate (295-5). LC-MS:[M+H]⁺=281.1.

To a solution of benzyl3-amino-3-(1-fluoroethyl)piperidine-1-carboxylate (295-5) (120 mg, 0.428mmol) in MeOH (15 ml) was added Pd(OH)₂ (60 mg) under N₂. The mixturewas then stirred under H₂ balloon for 3 hr. The mixture was filtered andthe filtrate was concentrated to give 3-(1-fluoroethyl)piperidin-3-amine(Intermediate 295-6). LC-MS: [M+H]+=147.1

Intermediate 297-6: 3-((methylthio)methyl)piperidin-3-amine

To a solution of 1-benzyl 3-ethyl3-((((trifluoromethyl)sulfonyl)oxy)methyl)piperidine-1,3-dicarboxylate(22-3) (18.0 g, 39.7 mmol, 1.0 eq.) in THF (200 mL) was added MeSNa(11.0 g, 159 mmol, 4.0 eq) at 0° C. The resulting mixture was stirred at15-20° C. for 16 hr. The reaction was quenched with water (300 mL), andextracted with EtOAc (300 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by Combi Flash (30% EtOAc in PE) to give 1-benzyl 3-ethyl3-((methylthio)methyl)piperidine-1,3-dicarboxylate (297-1). ¹H NMR (400MHz, CDCl₃) b ppm 7.25-7.45 (5H, m), 5.13 (2H, s), 4.05-4.25 (2H, m),3.80-4.00 (1H, m), 3.25-3.60 (3H, m), 2.60-2.85 (2H, m), 2.00-2.15 (4H,m), 1.55-1.75 (3H, m), 1.10-1.30 (3H, m).

A mixture of 1-benzyl 3-ethyl3-((methylthio)methyl)piperidine-1,3-dicarboxylate (297-1) (10.0 g, 28.5mmol, 1.0 eq.) and LiOHH₂O (12.0 g, 285 mmol, 10.0 eq.) in MeOH/THF/H₂O(120 mL, v/v/v=1/1/1) was stirred at 20° C. for 16 hr. The reaction wasconcentrated in vacuo. The residue was diluted with water (200 mL), andextracted with MTBE (100 mL). Then the pH of the aqueous layer wasadjusted to 5 by 1H HCl, and extracted with EtOAc (200 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give crude1-((benzyloxy)carbonyl)-3-((methylthio)methyl)piperidine-3-carboxylicacid (297-2). LC-MS: [M+H]⁺=324.1.

A mixture of1-((benzyloxy)carbonyl)-3-((methylthio)methyl)piperidine-3-carboxylicacid (297-2) (8.00 g, 24.7 mmol, 1.0 eq.), DPPA (7.50 g, 27.2 mmol, 1.1eq.) and Et₃N (5.00 g, 48.5 mmol, 2.0 eq.) in toluene (100 mL) wasstirred at 80° C. under N₂ for 1 hr. Then the reaction was concentratedin vacuo. The residue was dissolved in dioxane (50 mL) and 6N HCl (50mL), and the mixture was stirred for 16 hr at 25-30° C. The reaction wasconcentrated in vacuo. The pH of the aqueous layer was adjusted to 9 by1N NaOH. Then the mixture was extracted with EtOAc (200 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in DCM (100 mL), DIPEA(10.0 g, 74.2 mmol 3.0 eq) and Boc₂O (11.0 g, 48.4 mmol) were added. Theresulting mixture was stirred at 25-30° C. for 16 hr. The reaction wasconcentrated in vacuo. The residue was purified by Combi Flash (20%EtOAc in PE) to give benzyl3-((tert-butoxycarbonyl)amino)-3-((methylthio)methyl)piperidine-1-carboxylate (297-5). LC-MS: [M+H−100]*=295.1.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-3-((methylthio)methyl)piperidine-1-carboxylate(297-5) (2.37 g, 6.00 mmol, 1 eq.) in CH₃CN (50 mL) was added dropwiseTMSI (3.60 g, 18 mmol, 3 eq.) at about 0° C. After addition, thereaction mixture was stirred at the same temperature for 2 h. Thereaction mixture was carefully quenched with MeOH (20 mL) andHCl/dioxane (5 mL, 4M). The reaction mixture was concentrated. Water (20mL) was added and the mixture was extracted with MTBE (40 mL*4). Theaqueous layer was lyophilized to give crude3-((methylthio)methyl)piperidin-3-amine (Intermediate 297-6).

Intermediate 299-3: 2,2,2-Trifluoroacetaldehyde compound with1-(3-aminopiperidin-3-yl)-2,2,2-trifluoroethan-1-ol (1:1)

To a mixture of tert-butyl 3-nitropiperidine-1-carboxylate (5.0 g, 21.71mmol, 1.0 eq) and 2,2,2-trifluoroethane-1,1-diol (10.08 g, 86.86 mmol,4.0 eq) in THF (50 mL) was added K₂CO₃ (1.8 g, 13.03 mmol, 0.6 eq) at60° C. for 16 hours. 1N HCl (10 mL) was added to the mixture, andextracted with EA (40 mL*3). The combined organic layer was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive tert-butyl3-nitro-3-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate(299-1). H NMR: ¹H NMR (400 MHz, CDCl₃) b ppm 5.01-4.71 (m, 2H),4.67-4.34 (m, 1H), 4.07-3.35 (m, 2H), 2.88-2.13 (m, 2H), 1.95-1.52 (m,2H), 1.50-1.36 (m, 9H). LCMS: [M+H−56]⁺=273.3.

To a solution of tert-butyl3-nitro-3-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate(299-1) (4.0 g, 12.89 mmol, 1.0 eq) and NH₄Cl (3.45 g, 64.45 mmol, 5.0eq) in EtOH/H₂O (40 mL, v/v=4:1) was added Zn (8.43 g, 128.91 mmol, 10.0eq) at 25° C. under N₂. The mixture was stirred at 80° C. for 16 h,worked up under aqueous conditions, filtered and concentrated in vacuo.The crude was purified by column chromatography (PE:EA=10:1) to givetert-butyl3-amino-3-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate(299-2). H NMR: ¹H NMR (400 MHz, CDCl₃) δ ppm 4.05-3.93 (m, 1H),3.69-3.50 (m, 2H), 3.22-2.74 (m, 2H), 1.90-1.70 (m, 2H), 1.68-1.60 (m,2H), 1.47 (s, 9H).

To a solution of tert-butyl3-amino-3-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate(299-2) (1.2 g, crude) in DCM (10 mL) was added TFA (2 mL) drop-wiseunder the protection of nitrogen and the mixture was stirred at 25° C.for 2 hours. The mixture was concentrated to give2,2,2-trifluoroacetaldehyde compound with1-(3-aminopiperidin-3-yl)-2,2,2-trifluoroethan-1-ol (1:1) (Intermediate299-3).

Intermediate 300-6:(5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methanol

To a solution of tert-butyl 3-nitropiperidine-1-carboxylate (3 g, 13.03mmol) in THF (30 mL), was added K₂CO₃ (0.540 g, 3.91 mmol) and1-ethoxy-2,2-difluoroethanol (4.93 g, 39.1 mmol), the reaction mixturewas stirred at 55° C. for 18 h under N₂ atmosphere. he reaction mixturewas diluted with water, extracted with EtOAc (20 ml*3), the combinedorganic phase was washed with water (20 ml), brine (20 ml), dried overanhydrous sodium sulfate, concentrated in vacuum to give a residue. Theresidue was purified by flash chromatography (elution gradient: 0% to40% EtOAc in PE in 30 mins) to afford tert-butyl3-(2,2-difluoro-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate (300-1).LC-MS: [M+H]⁺=311.1

A solution of tert-butyl3-(2,2-difluoro-1-hydroxyethyl)-3-nitropiperidine-1-carboxylate (300-1)(2.0 g, 6.45 mmol) in BAST (20 mL) was stirred at 60° C. for 4 hoursunder N₂ atmosphere. The reaction mixture was diluted with water,extracted with EtOAc, the combined organic phase was washed with water,sat. NaHCO₃ solution, brine, dried over sodium sulfate, concentrated togive a crude product. The reaction mixture was diluted with water,extracted with EtOAc (20 ml*3), the combined organic phase was washedwith water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate,concentrated in vacuum to give a residue. The crude product was purifiedby flash chromatography (elution gradient: 0% to 30% EtOAc in PE in 30mins) to afford tert-butyl3-nitro-3-(1,2,2-trifluoroethyl)piperidine-1-carboxylate (300-2). LC-MS:[M+H]⁺=313.1

To a solution of tert-butyl3-nitro-3-(1,2,2-trifluoroethyl)piperidine-1-carboxylate (300-2) (1.36g, 4.35 mmol) in EtOH (30 mL) and water (15 mL), was added Fe (2.432 g,43.5 mmol) and NH₄Cl (1.165 g, 21.77 mmol), the reaction mixture wasstirred at 60° C. for 18 h under N₂ atmosphere. The reaction mixture wasfiltered and the filtrate was diluted with water, extracted with EtOAc(30 ml*3), the combined organic phase was washed with water (20 ml),brine (20 ml), dried over anhydrous sodium sulfate, concentrated invacuum to give a residue. The crude product was purified by flashchromatography (elution gradient: 0% to 50% EtOAc in PE in 30 mins) toafford tert-butyl3-amino-3-(1,2,2-trifluoroethyl)piperidine-1-carboxylate (300-3). LC-MS:[M+H]⁺=283.2.

To a solution of tert-butyl3-amino-3-(1,2,2-trifluoroethyl)piperidine-1-carboxylate (300-3) (700mg, 2.480 mmol) in DCM (12 mL), was added TFA (4 mL), the reactionmixture was stirred at rt for 1 h under N₂ atmosphere. The reactionmixture was concentrated to give3-(1,2,2-trifluoroethyl)piperidin-3-amine (300-4). LC-MS: [M+H]⁺=183.2.

To a solution of methyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate(Intermediate A) (0.847 g, 3.17 mmol) and3-(1,2,2-trifluoroethyl)piperidin-3-amine (300-4) (1.3 g, 3.17 mmol) inDMSO (30 mL) was added DIPEA (15 mL) at RT, the reaction mixture wasstirred at 80° C. for 8 hr under N₂ atmosphere. The reaction mixture wasdiluted with water, extracted with EtOAc (20 ml*3), worked up underaqueous conditions, and concentrated in vacuum to give a residue. Thecrude product was purified by flash chromatography (elution gradient: 0%to 30% EtOAc in PE in 30 mins) to afford methyl5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(300-5). LC-MS: [M+H]⁺=430.1.

To a solution of methyl5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(300-5) (0.65 g, 1.514 mmol) in THF (20 mL) and Methanol (20 mL), wasadded lithium chloride (1.284 g, 30.3 mmol) and sodium tetrahydroborate(1.145 g, 30.3 mmol) at RT, the reaction mixture was stirred at rt for 3h under N₂ atmosphere. The reaction mixture was diluted with water,extracted with EtOAc (20 ml*3), the combined organic phase was washedwith water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate,concentrated in vacuum to give a residue. The crude product was purifiedby flash chromatography (elution gradient: 10% to 40% EtOAc in PE in 30mins) to afford(5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methanol(Intermediate 300-6). LC-MS: [M+H]⁺=402.2.

To a solution of(5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methanol(Intermediate 300-6) (500 mg, 1.246 mmol), Intermediate B (501 mg, 1.495mmol) and triphenylphosphine (980 mg, 3.74 mmol) in THF (90 mL), wasadded DEAD (0.592 mL, 3.74 mmol) dropwise at 0° C., the reaction mixturewas stirred at 0° C. for 0.5 hr under N₂ atmosphere. The reactionmixture was diluted with water, extracted with EtOAc (20 ml*3), thecombined organic phase was washed with water (20 ml), brine (20 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to give aresidue. The crude product was purified by flash chromatography (elutiongradient: 0% to 10% MeOH in DCM in 50 mins) to afford Intermediate300-7. LC-MS: [M+H]⁺=719.2.

Intermediate 301-8:3-amino-1-(4-(chloromethyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol

To a solution of LDA (6.94 mL, 13.88 mmol) in THF (9 mL) was added asolution of 1-(tert-butyl) 3-methyl4-hydroxypiperidine-1,3-dicarboxylate (1.5 g, 5.78 mmol) in THF at −78°C. under N₂ atmosphere, after stirred for 10 min at this temperature, asolution of 1,1-difluoro-2-iodoethane (1.443 g, 7.52 mmol) in HMPA (5mL, 28.7 mmol) was added −15° C., the reaction mixture was stirred at RTfor 30 mins under N₂ atmosphere. The reaction mixture was diluted withwater, extracted with EtOAc (20 ml*3), the combined organic phase waswashed with water (20 ml), brine (20 ml), dried over anhydrous sodiumsulfate, concentrated in vacuum to give a residue. The residue waspurified by flash chromatography (elution gradient: 0% to 30% EtOAc inPE in 30 mins) to afford 1-(tert-butyl) 3-methyl3-(2,2-difluoroethyl)-4-hydroxypiperidine-1,3-dicarboxylate (301-1).LC-MS: [M+H]⁺=324.1.

To a solution of 1-(tert-butyl) 3-methyl3-(2,2-difluoroethyl)-4-hydroxypiperidine-1,3-dicarboxylate (301-1) (0.6g, 1.856 mmol) in methanol (5 mL) was added a solution of LiOH (700 mg,29.2 mmol) in Water (5 mL) at RT under N₂ atmosphere, the reaction wasstirred at RT for 5 hr. The pH of the reaction mixture was adjusted to 4by addition of 3M HCl solution, extracted with EtOAc (20 ml*3), thecombined organic phase was washed with water (20 ml), brine (20 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to givecrude1-(tert-butoxycarbonyl)-3-(2,2-difluoroethyl)-4-hydroxypiperidine-3-carboxylicacid (301-2). LC-MS: [M+H]⁺=310.1.

To a solution of1-(tert-butoxycarbonyl)-3-(2,2-difluoroethyl)-4-hydroxypiperidine-3-carboxylicacid (301-2) (0.4 g, 1.293 mmol) in Toluene (10 mL) was added DPPA(0.534 g, 1.940 mmol) and TEA (0.721 mL, 5.17 mmol) at RT under N₂atmosphere, the reaction was stirred at 100° C. for 18 hr. The reactionmixture was diluted with water, extracted with EtOAc (20 ml*3), thecombined organic phase was washed with water (20 ml), brine (20 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to give aresidue. The residue was purified by flash chromatography (elutiongradient: 0% to 50% EtOAc in PE in 30 mins) to afford tert-butyl3a-(2,2-difluoroethyl)-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (303-3). 1H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H),6.43-5.89 (m, 1H), 4.41-4.15 (m, 2H), 4.13 (dt, J=12.9, 2.5 Hz, 1H),3.03-2.75 (m, 2H), 2.03-1.74 (m, 4H), 1.39 (s, 9H). LC-MS: [M+H]⁺=307.1.

To a solution of tert-butyl3a-(2,2-difluoroethyl)-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (301-3) (400 mg, 1.306 mmol) in DCM (9 mL) was addedTFA (3 mL, 38.9 mmol) at RT under N₂ atmosphere, the reaction wasstirred at RT for 1 hr. The reaction mixture was concentrated in vacuumto give crude 3a-(2,2-difluoroethyl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one (301-4). LC-MS: [M+H]⁺=207.1.

To a solution of methyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate(Intermediate A) (259 mg, 0.970 mmol) and3a-(2,2-difluoroethyl)hexahydrooxazolo[4,5-c]pyridin-2 (3H)-one (301-4)in DMSO (10 mL) was added DIPEA (10 mL, 57.3 mmol) at RT under N₂atmosphere, the reaction was stirred at 120° C. for 18 hr. The reactionmixture was diluted with water, extracted with EtOAc (20 ml*3), thecombined organic phase was washed with water (20 ml*3), brine (20 ml),dried over anhydrous sodium sulfate, concentrated in vacuum to give aresidue. The residue was purified by flash chromatography (elutiongradient: 0% to 10% MeOH in DCM in 30 mins) to afford methyl5-(3a-(2,2-difluoroethyl)-2-oxohexahydrooxazolo[4,5-c]pyridin-5(4H)-yl)-2-(3,4-difluorophenyl)isonicotinate (301-5). LC-MS:[M+H]⁺=454.1.

To a solution of methyl5-(3a-(2,2-difluoroethyl)-2-oxohexahydrooxazolo[4,5-c]pyridin-5(4H)-yl)-2-(3,4-difluorophenyl)isonicotinate (301-5) (40 mg, 0.088 mmol)in THF (5 ml) and Methanol (5 ml) was added LiCl (74.8 mg, 1.764 mmol)and NaBH₄ (33.4 mg, 0.882 mmol) at RT under N₂ atmosphere, the reactionwas stirred at RT for 5 hr. The reaction mixture was diluted with water,extracted with EtOAc (20 ml*3), the combined organic phase was washedwith water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate,concentrated in vacuum to give a residue. The residue was purified byflash chromatography (elution gradient: 0% to 10% MeOH in DCMin 30 mins)to afford3a-(2,2-difluoroethyl)-5-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one (301-6). LC-MS: [M+H]⁺=426.2.

To a solution of3a-(2,2-difluoroethyl)-5-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one (301-6) (100 mg, 0.235 mmol) in MeOH (10 mL) and Water (10 mL)was added KOH (132 mg, 2.351 mmol) at RT under N₂ atmosphere, thereaction was stirred at 100° C. for 18 hr. The reaction mixture wasdiluted with water, extracted with EtOAc (20 ml*3), the combined organicphase was washed with water (20 ml), brine (20 ml), dried over anhydroussodium sulfate, concentrated in vacuum to give a residue. The residuewas purified by flash chromatography (elution gradient 0% to 10% MeOH inDCM in 30 mins) to afford3-amino-3-(2,2-difluoroethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-4-ol(301-7). LC-MS: [M+H]⁺=400.1.

To a solution of3-amino-3-(2,2-difluoroethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-4-ol(301-7) (130 mg, 0.325 mmol) in DCM (10 mL) was added thionyl chloride(0.119 mL, 1.627 mmol) at 0° C. under N₂ atmosphere, the reaction wasstirred at RT for 5 hr. The reaction was quenched with 5 ml of sat.K₂CO₃ aqueous solution at 0° C. The reaction mixture was extracted withDCM (20 ml*3), the combined organic phase was washed with water (20 mL),brine (20 mL), dried over anhydrous sodium sulfate, concentrated invacuum to give crude3-amino-1-(4-(chloromethyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol(Intermediate 301-8). LC-MS: [M+H]⁺=418.1.

Intermediate 302-9:3-amino-3-(6-chloropyridin-2-yl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-4-ol

To a solution of m-CPBA (23.17 g, 94 mmol) and 2-chloro-6-iodopyridine(15 g, 62.6 mmol) in DCM (450 mL) was added TfOH (22.25 mL, 251 mmol)dropwise at 0° C. And then the reaction mixture was stirred at RT for 2hr, mesitylene (9.54 mL, 68.9 mmol) was added dropwise at 0° C., thereaction mixture was stirred at RT for 18 hr under N₂ atmosphere. Thesolvent was removed in vacuo to give a crude product. The crude productwas recrystallized in Et₂O at −20° C. to afford(6-chloropyridin-2-yl)(mesityl)iodonium trifluoromethanesulfonate(302-1). LC-MS: [M+H]⁺=358.

To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate(1.3 g, 5.05 mmol) in DMF (30 mL) was added potassium tert-butoxide(0.680 g, 6.06 mmol) at RT, after the reaction mixture was stirred at RTfor 10 mins, (6-chloropyridin-2-yl)(mesityl)iodoniumtrifluoromethanesulfonate (intermediate 302-1) (3.52 g, 5.56 mmol) wasadded at rt, the reaction mixture was stirred at rt for 18 hr under N₂atmosphere. The reaction mixture was diluted with water, extracted withEtOAc, the combined organic phase was washed with water, brine, driedover sodium sulfate, concentrated to give a crude product. The crudeproduct was purified by flash chromatography (elution gradient: 0% to30% EtOAC in Hexane in 30 mins) to afford 1-(tert-butyl) 3-methyl3-(6-chloropyridin-2-yl)-4-oxopiperidine-1,3-dicarboxylate (302-2).LC-MS: [M+H]⁺=369.0

To a solution of 1-(tert-butyl) 3-methyl3-(6-chloropyridin-2-yl)-4-oxopiperidine-1,3-dicarboxylate (intermediate302-2) (1.0 g, 2.71 mmol) in MeOH (30 mL) was added sodiumtetrahydroborate (0.205 g, 5.42 mmol) at 0° C., the reaction mixture wasstirred at 0° C. for 30 mins. The reaction mixture was diluted withwater, extracted with EtOAc, the combined organic phase was washed withwater, brine, dried over sodium sulfate, concentrated to give a crudeproduct. The crude product was purified by flash chromatography (elutiongradient: 0% to 30% EtOAC in Hexane in 30 mins) to afford 1-(tert-butyl)3-methyl 3-(6-chloropyridin-2-yl)-4-hydroxypiperidine-1,3-dicarboxylate(302-3). LC-MS: [M+H]⁺=371.0

To a solution of 1-(tert-butyl) 3-methyl3-(6-chloropyridin-2-yl)-4-hydroxypiperidine-1,3-dicarboxylate (302-3)(0.9 g, 2.427 mmol) in methanol (5 mL) and water (5 mL) was added LiOH(0.581 g, 24.27 mmol) at RT, the reaction mixture was stirred at RT for5 hr under N₂ atmosphere. The pH of reaction mixture was adjusted to 4by addition of 5M HCl aqeuous solution, extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over sodiumsulfate, concentrated to give a crude product. The crude product waspurified by flash chromatography (elution gradient: 0% to 10% MeOH inDCM in 30 mins) to afford1-(tert-butoxycarbonyl)-3-(6-chloropyridin-2-yl)-4-hydroxypiperidine-3-carboxylicacid (302-4). LC-MS: [M+H]⁺=357.1.

To a solution of1-(tert-butoxycarbonyl)-3-(6-chloropyridin-2-yl)-4-hydroxypiperidine-3-carboxylicacid (302-4) (0.8 g, 2.242 mmol) in toluene (20 mL) and was added DPPA(0.926 g, 3.36 mmol) and TEA (1.250 mL, 8.97 mmol) at RT, after thereaction mixture was stirred at 100° C. for 3 h under N₂ atmosphere,methanol (0.091 mL, 2.242 mmol) was added, the reaction mixture wasstirred at 100° C. for 18 hr under N₂ atmosphere. The reaction mixturewas diluted with water, extracted with EtOAc, the combined organic phasewas washed with water, brine, dried over sodium sulfate, concentrated togive a crude product. The crude product was purified by flashchromatography (elution gradient: 0% to 10% MeOH in DCM in 30 mins) toafford tert-butyl3a-(6-chloropyridin-2-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (302-5). LC-MS: [M+H]⁺=354.1.

To a solution of tert-butyl3a-(6-chloropyridin-2-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (302-5) (400 mg, 0.113 mmol) in DCM (9 mL) and wasadded TFA (3 ml) at rt, the reaction mixture was stirred at rt for 3 h.The reaction mixture was concentrated to give crude3a-(6-chloropyridin-2-yl)hexahydrooxazolo[4,5-c]pyridin-2 (3H)-one(302-6). LC-MS: [M+H]⁺=254.1

To a solution of methyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate(Intermediate A) (87 mg, 0.326 mmol) and3a-(6-chloropyridin-2-yl)hexahydrooxazolo[4,5-c]pyridin-2 (3H)-one(302-6) (120 mg, 0.326 mmol) in DMSO (5 mL), was added DIPEA (5 mL), thereaction mixture was stirred at 100° C. for 5 hr under N₂ atmosphere.The reaction mixture was diluted with water, extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over sodiumsulfate, concentrated to give a crude product. The crude product waspurified by flash chromatography (elution gradient: 0% to 10% MeOH inDCM in 30 mins) to afford methyl5-(3a-(6-chloropyridin-2-yl)-2-oxohexahydrooxazolo[4,5-c]pyridin-5(4H)-yl)-2-(3,4-difluorophenyl)isonicotinate (302-7). LC-MS:[M+H]⁺=501.1

To a solution of methyl5-(3a-(6-chloropyridin-2-yl)-2-oxohexahydrooxazolo[4,5-c]pyridin-5(4H)-yl)-2-(3,4-difluorophenyl)isonicotinate (302-7) (70 mg, 0.140 mmol)in methanol (5 mL) and THF (5 mL), was added lithium chloride (59.2 mg,1.398 mmol) and sodium tetrahydroborate (52.9 mg, 1.398 mmol), thereaction mixture was stirred at rt for 5 hr under N₂ atmosphere. Thereaction mixture was diluted with water, extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over sodiumsulfate, concentrated to give a crude product. The crude product waspurified by flash chromatography (elution gradient: 0% to 10% MeOH inDCM in 30 mins) to afford3a-(6-chloropyridin-2-yl)-5-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one (302-8). LC-MS: [M+H]⁺=473.1.

To a solution of3a-(6-chloropyridin-2-yl)-5-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one (302-8) (50 mg, 0.106 mmol) in methanol (5 mL) and was added asolution of KOH (59.3 mg, 1.057 mmol) in Water (5 ml) at rt, thereaction mixture was stirred at 100° C. for 8 hr under N₂ atmosphere.The reaction mixture was diluted with water, extracted with EtOAc, thecombined organic phase was washed with water, brine, dried over sodiumsulfate, concentrated to give a crude product. The crude product waspurified by flash chromatography (elution gradient: 0% to 10% MeOH inDCM in 30 mins) to afford3-amino-3-(6-chloropyridin-2-yl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-4-ol(Intermediate 302-9). LC-MS: [M+H]⁺=447.1

Intermediate 303-3: 3-(2,2,2-trifluoroethyl)piperidin-3-amine

Togni reagent (6.42 g, 19.46 mmol) and tetrakis(acetonitrile)copper(I)hexafluorophosphate (483 mg, 1.297 mmol) were dissolved in DMA (50 ml)under N₂. Then reagent 1 (3 g, 12.97 mmol) and TMSN₃ (2.99 g, 25.9 mmol)was added. The mixture was stirred at rt overnight. The mixture wastreated with EA (50 ml) and H₂O (50 ml). The layers were separated andthe aqueous layer was extracted with EA (30 ml*3). The combined organiclayers were washed with brine (20 ml), dried over Na₂SO₄ and filtered.The filtrate was concentrated and the residue was purified, eluting withEA in n-hexane (0 to 20%) to give benzyl3-azido-3-(2,2,2-trifluoroethyl)piperidine-1-carboxylate (303-1). ¹H NMR(400 MHz, CDCl₃ 7.31-7.51 (m, 1H), 5.03-5.34 (m, 1H), 3.86 (d, J=12.80Hz, 1H), 3.20 (d, J=13.55 Hz, 1H), 2.39 (br. s., 1H), 1.92-2.01 (m, 1H),1.81 (d, J=9.54 Hz, 2H)), 1.54-1.72 (m, 1H).

To a solution of benzyl3-azido-3-(2,2,2-trifluoroethyl)piperidine-1-carboxylate (303-1) (1.3 g,0.15 mmol) in MeOH (20 ml) was added indium powder (1.3 g, 11.4 mmol)and NH₄Cl (0.609 g, 11.38 mmol). The mixture was heated to reflux undera sealed tube for 2 hrs. The mixture was cooled to rt and filtered. Thefiltrate was concentrated. The residue was purified via prep. HPLC togive benzyl 3-amino-3-(2,2,2-trifluoroethyl)piperidine-1-carboxylate TFAsalt (303-2). LC-MS: [M+H]⁺=316.9.

To a solution of benzyl3-amino-3-(2,2,2-trifluoroethyl)piperidine-1-carboxylate (303-2) (500mg, 1.58 mmol) in MeOH (40 ml) was added Pd(OH)₂ (222 mg, 1.581 mmol)under N₂. The mixture was then stirred under H₂ balloon for 3 hr. Themixture was filtered and the filtrate was concentrated to3-(2,2,2-trifluoroethyl)piperidin-3-amine (Intermediate 303-3). ¹H NMR(CDCl₃) δ: 3.57-3.35 (m, 4H), 3.02-2.84 (m, 2H), 2.43 (q, J=11.1 Hz,2H), 2.25 (dddd, J=17.3, 13.2, 8.6, 4.2 Hz, 1H), 1.96 (d, J=13.1 Hz,1H), 1.84-1.59 (m, 2H) LC-MS: [M+H]⁺=183.0.

Intermediate 304-7: Methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-ethynylpiperidin-3-yl)carbamate

To a solution of 1-benzyl 3-ethyl 3-formylpiperidine-1,3-dicarboxylate(6.5 g, 20.4 mmol, 1.0 eq.) and dimethyl(1-diazo-2-oxopropyl)phosphonate (7.8 g, 40.8 mmol, 2.0 eq.) in drymethanol (120 mL) was added K₂CO₃ (8.5 g, 61.2 mmol, 3.0 eq.). Themixture was stirred at 1˜7° C. for 18 h, filtered and the filtrate wasconcentrated. The residue was purified by flash chromatography(PE/EA=70/30) to give 1-benzyl 3-methyl3-ethynylpiperidine-1,3-dicarboxylate (304-1). ¹H NMR (CDCl₃ 400 MHz): δ7.48-7.28 (m, 5H), 5.14 (s, 2H), 4.25-4.09 (m, 1H), 4.00-3.84 (m, 1H),3.73 (s, 3H), 3.48 (d, J=12.8 Hz, 1H), 3.14-2.97 (m, 1H), 2.20 (s, 1H),2.06-1.80 (m, 3H), 1.64-1.60 (m, 1H).

To a solution of 1-benzyl 3-methyl 3-ethynylpiperidine-1,3-dicarboxylate(intermediate 304-1) (3.1 g, 10.3 mmol, 1.0 eq.) in THF (50 mL) andwater (15 mL) was added LiOH.H₂O (1.7 g, 41.1 mmol, 4.0 eq.). Themixture was stirred at 50° C. for 2 h. The mixture was diluted withwater (100 mL), extracted with EA (80 mL). The aqueous layer wasacidified to pH=2 with 1 N HCl (aq.). The suspension was extracted withDCM (80 mL*2), dried over Na₂SO₄, concentrated to give crude1-((benzyloxy)carbonyl)-3-ethynylpiperidine-3-carboxylic acid (304-2).¹H NMR (CDCl₃ 400 MHz): δ 10.03 (brs, 1H), 7.40-7.31 (m, 5H), 5.17 (s,2H), 4.29-4.16 (m, 1H), 4.02-3.88 (m, 1H), 3.49 (d, J=12 Hz, 1H),3.15-2.98 (m, 1H), 2.24 (s, 1H), 2.12-2.06 (m, 1H), 2.04-1.92 (m, 2H),1.67-1.64 (m, 1H).

To a solution of1-((benzyloxy)carbonyl)-3-ethynylpiperidine-3-carboxylic acid (304-2)(2.7 g, 9.4 mmol, 1.0 eq.) in DCM (125 mL) was added NH₄Cl (1 g, 18.8mmol, 2.0 eq.), HATU (7.1 g, 18.8 mmol, 2.0 eq.) and DIEA (4.9 g, 37.6mmol, 4 eq.). The resulting mixture was stirred at 25° C. for 16 h. Themixture was washed with water (100 mL) and brine (150 mL), dried overNa₂SO₄, concentrated. The residue was purified by flash chromatography(PE/EA=50/50) to give benzyl3-carbamoyl-3-ethynylpiperidine-1-carboxylate (304-3). ¹H NMR (400 MHz,CDCl₃): δ 7.35-7.21 (m, 5H), 6.68-6.59 (d, J=36.8 Hz, 1H), 5.87 (s, 1H),5.11-5.01 (m, 2H), 4.25-4.02 (m, 2H), 3.20-3.14 (m, 1H), 2.89-2.64 (m,1H), 2.26 (d, J=20.8 Hz, 1H), 2.12-1.71 (m, 3H), 1.57 (d, J=10 Hz, 1H).

To a solution of benzyl 3-carbamoyl-3-ethynylpiperidine-1-carboxylate(304-3) (2.5 g, 8.7 mmol, 1.0 eq.) in methanol (100 mL) was added KOH(1.2 g, 21.8 mmol, 2.5 eq.). Then PhI(OAc)₂ (2.8 g, 8.7 mmol, 1.0 eq.)was added. The resulting mixture was stirred at 3˜10° C. for 30 min. Thecolor turned from colorless to yellow. The reaction was concentrated,diluted with water (150 mL), extracted with EA (100 mL*2), dried overNa₂SO₄ and concentrated. The residue was purified by flashchromatography (PE/EA=70/30) to give benzyl3-ethynyl-3-((methoxycarbonyl)amino) piperidine-1-carboxylate (304-4).¹H NMR (400 MHz, CD₃OD): δ 7.48-7.30 (m, 5H), 5.20-4.86 (m, 3H),4.13-3.83 (m, 2H), 3.65 (s, 3H), 3.51-3.22 (m, 2H), 2.69-2.30 (m, 2H),1.95-1.64 (m, 3H).

A mixture of benzyl3-ethynyl-3-((methoxycarbonyl)amino)piperidine-1-carboxylate (304-4)(800 mg, 2.53 mmol, 1.0 eq.) and TFA (10 mL) in DCM (10 mL) was stirredat 75° C. for 12 h. The mixture was concentrated and diluted with DCM(20 mL), poured into saturated NaHCO₃ solution (50 mL), extracted withCHCl₃/i-PrOH=3/1 (50 mL*4), dried over Na₂SO₄, concentrated to givecrude methyl (3-ethynylpiperidin-3-yl)carbamate (304-5). LCMS:[M+H]⁺=182.9.

To a mixture of methyl (3-ethynylpiperidin-3-yl)carbamate (304-5) (600mg, 2.53 mmol, 1.0 eq.) and methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate (Intermediate A) (670 mg,2.53 mmol, 1.0 eq.) in DMSO (10 mL) was added DIEA (2.3 g, 7.0 eq.).Then the mixture was stirred at 120° C. for 2.5 h. The mixture wascooled and diluted with water (100 mL), extracted with EA (50 mL*2),washed with brine (100 mL), dried over Na₂SO₄, concentrated. The residuewas purified by flash chromatography (PE/EA=10/1 to 70/30) to givemethyl2-(3,4-difluorophenyl)-5-(3-ethynyl-3-((methoxycarbonyl)amino)piperidin-1-yl)isonicotinate(304-6). LCMS: [M+H]⁺=430.2.

To a solution of methyl2-(3,4-difluorophenyl)-5-(3-ethynyl-3-((methoxycarbonyl)amino)piperidin-1-yl)isonicotinate (intermediate 304-6) (280 mg, 0.652 mmol,1.0 eq.) in dry THF (12 mL) was added L-selectride (3.9 mL) dropwise at0° C. under N₂. The solution was stirred at 0° C. for 30 min. Themixture was quenched with saturated NH₄Cl solution (30 mL) and dilutedwith water (100 mL), extracted with EA (50 mL*2), dried over Na₂SO₄,concentrated. The residue was purified by flash chromatography(PE/EA=1/1) to give methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-ethynylpiperidin-3-yl)carbamate(Intermediate 304-7). LCMS: 402.1 [M+H]⁺=402.1.

Intermediate 305-5: 3-(difluoromethyl)piperidin-3-amine

To a solution of 1-benzyl 3-ethyl 3-formylpiperidine-1,3-dicarboxylate(7.0 g, 21.9 mmol, 1.0 eq.) in DCM (100 mL) at 0° C. under N₂ atmospherewas added DAST (14.1 g, 87.8 mmol, 4.0 eq.) dropwise. The reaction wasallowed to warm to 10° C. and stirred for 16 h. The reaction was cooledto 0° C. and quenched with aq.NaHCO₃ (100 mL) carefully. The mixture wasextracted with DCM (50 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column (PE/EA=10/1) to afford 4.0 g crudeproduct, which was further purified by prep-HPLC (0.1% TFA as additive)to give 1-benzyl 3-ethyl 3-(difluoromethyl)piperidine-1,3-dicarboxylate(305-1). ¹H NMR (400 MHz, CDCl₃): δ 7.45-7.28 (m, 5H), 5.89 (t, J=15.2Hz, 1H), 5.16 (s, 2H), 4.55-4.37 (m, 1H), 4.27-4.05 (m, 2H), 4.04-3.87(m, 1H), 3.28-3.10 (m, 1H), 3.05-2.90 (m, 1H), 2.25-2.10 (m, 1H),1.80-1.60 (m, 3H), 1.30-1.12 (m, 3H).

To a mixture of 1-benzyl 3-ethyl3-(difluoromethyl)piperidine-1,3-dicarboxylate (305-1) (2.6 g, 7.62mmol, 1 eq.) in THF (10 mL), MeOH (10 mL) and H₂O (10 mL) was addedLiOH.H₂O (3.2 g, 76.2 mmol, 10 eq.). The reaction was stirred at 40° C.for 16 h. The reaction mixture was cooled and acidified to pH=3 with 6MHCl, then extracted with DCM (30 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto give1-((benzyloxy)carbonyl)-3-(difluoromethyl)piperidine-3-carboxylic acid(305-2). 1H NMR (400 MHz, CDCl₃): δ 7.45-7.25 (m, 5H), 5.93 (t, J=15.6Hz, 1H), 5.17 (s, 2H), 4.55-4.42 (m, 1H), 4.05-3.95 (m, 1H), 3.25-3.15(m, 1H), 3.05-2.95 (m, 1H), 2.28-2.15 (m, 1H), 1.85-1.68 (m, 3H). LCMS:[M+H]⁺=314.

To a mixture of1-((benzyloxy)carbonyl)-3-(difluoromethyl)piperidine-3-carboxylic acid(305-2) (3.4 g, 10.9 mmol, 1.0 eq.) and Et₃N (2.2 g, 21.72 mmol, 2.0eq.) in toluene (50 mL) under N₂ atmosphere was added DPPA (3.3 g, 11.9mmol, 1.1 eq.). The reaction was heated and stirred at 60° C. for 3 h.The reaction mixture was cooled and diluted with EtOAc (100 mL), thenwashed with H₂O (50 mL×2). The organic layer was dried over Na₂SO₄,filtered and concentrated to give the crude benzyl3-(difluoromethyl)-3-isocyanatopiperidine-1-carboxylate (305-3).

To a solution of benzyl3-(difluoromethyl)-3-isocyanatopiperidine-1-carboxylate (305-3) (3.4 g,10.9 mmol, 1.0 eq.) in dioxane (10 mL) was added 6M HCl (10 mL). Thereaction was stirred at 40° C. for 16 h. The reaction mixture wasconcentrated to remove dioxane, then diluted with H₂O (20 mL) andextracted with EtOAc (20 mL). The aqueous phase was basified to pH=10with aq.NaOH. The mixture was extracted with DCM (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to givebenzyl 3-amino-3-(difluoromethyl)piperidine-1-carboxylate (305-4). ¹HNMR (400 MHz, CDCl₃): δ 7.45-7.28 (m, 5H), 5.56 (t, J=16.0 Hz, 1H), 5.15(s, 2H), 3.88-3.80 (m, 1H), 3.65-3.50 (m, 1H), 3.35-3.00 (m, 2H),1.87-1.65 (m, 4H), 1.30-1.15 (m, 2H). LCMS: [M+H]⁺=285.

A mixture of benzyl 3-amino-3-(difluoromethyl)piperidine-1-carboxylate(intermediate 305-4) (1.8 g, 6.33 mmol, 1 eq.) and Pd/C (10%, 1.5 g) inEtOH (36 mL) was hydrogenated under H₂ balloon for 3 h. The reactionmixture was filtered and the filtrate was concentrated to dryness togive 3-(difluoromethyl)piperidin-3-amine (Intermediate 305-5). ¹H NMR(400 MHz, CD₃OD): δ5.68 (t, J=16.4 Hz, 1H), 5.15 (s, 2H), 2.88-2.75 (m,1H), 2.80-2.65 (m, 1H), 2.63-2.52 (m, 2H), 1.80-1.65 (m, 2H), 1.62-1.51(m, 2H).

Intermediate 306-9: tert-butyl(tert-butoxycarbonyl)(9-((5-((3R,5R)-3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate

A mixture of ethyl 5-bromonicotinate (20.0 g, 86.9 mmol, 1 eq.), NH₂Boc(12.2 g, 104 mmol, 1.2 eq.), Xant-Phos (1.60 g, 2.77 mmol, 0.03 eq.),Pd₂(dba)₃ (1.60 g, 1.75 mmol, 0.02 eq.) and Cs₂CO₃ (40.0 g, 123 mmol,1.4 eq.) and dioxane (300 mL) was stirred at 110° C. under N₂ atmospherefor 16 h. Then the reaction mixture was concentrated to dryness. Water(800 mL) was added and the reaction mixture was extracted with EtOAc(300 mL*2). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycombi flash (EtOAc/PE=0-40%) to give ethyl5-((tert-butoxycarbonyl)amino)nicotinate (306-1). ¹H NMR (400 MHz,CDCl₃): δ 8.89 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.8 Hz, 1H), 8.47 (s, 1H),6.99 (brs, 1H), 4.41 (q, J=7.6 Hz, 2H), 1.54 (s, 9H), 1.40 (t, J=7.2 Hz,3H).

To a solution of LAH (3.05 g, 80.3 mmol, 1.6 eq.) in THF (200 mL) wasadded dropwise a solution of ethyl5-((tert-butoxycarbonyl)amino)nicotinate (306-1) (13.5 g, 50.7 mmol, 1eq.) in THF (200 mL) at 0° C. After addition, the reaction mixture wasstirred at about 0° C. for 2 h. The reaction mixture was carefullyquenched with water (3 mL), 10% NaOH (3 mL) and water (10 mL). Thereaction mixture was filtered and the filtrate was concentrated todryness. The residue was purified by combi flash (EtOAc/PE=0-100%) togive tert-butyl (5-(hydroxymethyl)pyridin-3-yl)carbamate (306-2). ¹HNMR(400 MHz, CDCl₃): δ 8.33 (d, J=2.4 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.01(s, 1H), 7.23 (brs, 1H), 4.69 (s, 2H), 1.53 (s, 9H).

A mixture of tert-butyl (5-(hydroxymethyl)pyridin-3-yl)carbamate(intermediate 306-2) (10.0 g, 44.6 mmol, 1 eq.) and PtO₂ (3.0 g) in AcOH(3 mL) and EtOH (300 mL) was hydrogenated under H₂ atmosphere (50 psi)at 50° C. for 7 days. The reaction mixture was filtered and the filtratewas concentrated to dryness to give tert-butyl(5-(hydroxymethyl)piperidin-3-yl)carbamate (306-3). LC-MS: [M+H]⁺=230.1

To a suspension of tert-butyl (5-(hydroxymethyl)piperidin-3-yl)carbamate(306-3) (10.0 g, impure, 1 eq.) and NaHCO₃ (10.9 g, 130 mmol, 3 eq.) inTHF (100 mL) and H₂O (100 mL) was added dropwise CbzCl (8.20 g, 47.4mmol, 1.1 eq.) at about 0° C. After addition, the reaction mixture wasstirred at about 20° C. for 16 h. The reaction mixture was poured intowater (400 mL) and extracted with EtOAc (200 mL*3). The combined organiclayers were dried over Na₂SO₄, and concentrated to dryness. The residuewas purified by combi flash (EtOAc/PE=0-70%) to give benzyl3-((tert-butoxycarbonyl)amino)-5-(hydroxymethyl)piperidine-1-carboxylate(306-4). ¹H NMR (400 MHz, CDCl₃): δ 7.40-7.25 (m, 5H), 5.25-5.05 (m,2H), 4.80-4.10 (m, 3H), 3.65-3.40 (m, 4H), 2.60-2.45 (m, 1H), 2.15-2.00(m, 1H), 1.98-1.65 (m, 2H), 1.43 (s, 9H), 1.15-1.00 (m, 1H). LC-MS:[M+Na]⁺=387.1.

To a mixture of benzyl3-((tert-butoxycarbonyl)amino)-5-(hydroxymethyl)piperidine-1-carboxylate(306-4) (3.50 g, 9.60 mmol, 1.0 eq.) in THF (60 mL) was added Et₃N (13.6g, 134 mmol, 14.0 eq.), FSO₂(CF₂)₃CF₃ (5.80 g, 19.2 mmol, 2.0 eq.) andTEA.3HF (6.19 g, 38.4 mmol, 4.0 eq.). The reaction mixture was stirredat 25° C. for 12 hours. The reaction mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography (Eluents:PE/EA 10/1 to 3/1) to give benzyl3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidine-1-carboxylate(306-5). LC-MS: [M+Na]⁺=389.1.

To a solution of benzyl3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidine-1-carboxylate(306-5) (2.50 g, 6.83 mmol, 1.0 eq.) in MeOH (30 mL) was added Pd(OH)₂/C(250 mg, 10% wt). The reaction mixture was stirred at 25° C. for 1 hour.The mixture was filtered and the filtrate was concentrated in vacuo togive tert-butyl (5-(fluoromethyl)piperidin-3-yl)carbamate (305-6).LC-MS: [M+H]⁺=233.1.

To a solution of tert-butyl (5-(fluoromethyl)piperidin-3-yl)carbamate(306-6) (1.50 g, 6.51 mmol, 1.0 eq.) in DMSO (15 mL) was added DIEA(5.89 g, 45.6 mmol, 7.0 eq.) and methyl5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinate (Intermediate D)(1.82 g, 6.51 mmol, 1.0 eq.). The reaction mixture was stirred at 120°C. under N₂ for 3 hours. The reaction mixture was diluted with water(100 mL) and extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (PE/EA 10/1 to 2/1) and further purified byprep-HPLC (0.05% NH₃.H₂O as additive) to afford methyl5-((3R,5R)-3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)isonicotinate(306-7). ¹H NMR (400 MHz, CD₃OD): δ 8.45 (s, 1H), 7.93 (s, 1H),7.76-7.67 (m, 2H), 7.19 (t, J=8.4 Hz, 1H), 4.51 (d, J=6.0 Hz, 1H), 4.39(d, J=6.0 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.92-3.86 (m, 1H),3.35-3.24 (m, 1H), 3.20-3.08 (m, 2H), 3.01-2.92 (m, 1H), 2.46-2.31 (m,1H), 1.84-1.76 (m, 1H), 1.64-1.54 (m, 1H), 1.42-1.41 (m, 10H). LC-MS:[M+H]⁺=492.2

To a mixture of methyl5-((3R,5R)-3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)isonicotinate(306-7) (120 mg, 0.24 mmol, 1.0 eq.) and LiCl (102 mg, 2.44 mmol, 10eq.) in THF (2 mL) and MeOH (2 mL) was added NaBH₄ (181 mg, 4.88 mmol,20 eq.) in small portions. After addition, the mixture was stirred at25° C. for 1 hour. Then water (20 mL) was added, and the mixture wasextracted with EtOAc (10 mL×3). The combined organic phase were washedwith brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give tert-butyl((3R,5R)-1-(6-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)-5-(fluoromethyl)piperidin-3-yl)carbamate(306-8). LC-MS: [M+H]⁺=464.3

To a mixture of tert-butyl((3R,5R)-1-(6-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)-5-(fluoromethyl)piperidin-3-yl)carbamate(intermediate 306-8) (100 mg, 0.22 mmol, 1.0 eq.), Intermediate B (109mg, 0.32 mmol, 1.5 eq.), n-Bu₃P (66.0 mg, 0.32 mmol, 1.5 eq.) and THF(10 mL) was added DIAD (66.0 mg, 0.32 mmol, 1.5 eq.) dropwise. Afteraddition, the mixture was stirred at 25° C. for 12 hours under N₂. Themixture was concentrated in vacuo. The residue was purified by silicagel column (PE/EA=5:1 to 1:1) to give tert-butyl(tert-butoxycarbonyl)(9-((5-((3R,5R)-3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 306-9). LC-MS: [M+Na]⁺=803.4

Intermediate 311-11: Methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate

To a solution of 3-aminopicolinic acid (50 g, 360 mmol, 1.0 eq) inanhydrous MeOH (500 mL) was added conc.H₂SO₄ (106 g, 1090 mmol, 3.0 eq)dropwise. The reaction was stirred at 80° C. for 48 h. SOCI₂ (130 g,1090 mmol, 3.0 eq) was added to the reaction and stirred at 80° C. foranother 48 h. The reaction was concentrated and diluted with water (500mL), basified with K₂CO₃(s) to PH=9, extracted with EA (500 mL×3),washed with brine (500 mL), dried over Na₂SO₄, concentrated to givemethyl 3-aminopicolinate (311-1). ¹H NMR (400 MHz, CDCl₃) 5=8.04 (d,J=4.3 Hz, 1H), 7.20 (dd, J=4.3, 8.4 Hz, 1H), 7.04 (dd, J=1.3, 8.4 Hz,1H), 5.76 (br s, 2H), 3.98-3.92 (m, 3H).

To a solution of methyl 3-aminopicolinate (311-1) (27 g, 180 mmol, 1.0eq) and K₂CO₃ (48 g, 350 mmol, 2.0 eq) in MeCN (500 mL) was added methylcarbonochloridate (33 g, 350 mmol, 2.0 eq) at 20° C. for 18 h. Thereaction mixture was diluted with water (500 mL), concentrated. Theresidue was acidified with 1 N HCl to PH=3, extracted with EA (500mL×3), washed with sat.NaHCO₃ (500 mL) and brine (300 mL), dried overNa₂SO₄, concentrated to give methyl 3-((methoxycarbonyl)amino)picolinate(311-2). ¹H NMR (400 MHz, CDCl₃) 5=10.39 (br s, 1H), 8.82 (dd, J=1.4,8.7 Hz, 1H), 8.34 (dd, J=1.5, 4.4 Hz, 1H), 7.51-7.40 (m, 1H), 3.99 (s,3H), 3.78 (s, 3H).

A solution of methyl 3-((methoxycarbonyl)amino)picolinate (intermediate311-2) (22 g, 105 mmol, 1.0 eq) and PtO₂ (5 g, 23% wt) in AcOH (220 mL)was stirred at 25° C. and 5 MPa under H₂ for 144 h. The reaction mixturewas filtered and concentrated to give methyl(2S,3R)-3-((methoxycarbonyl)amino)piperidine-2-carboxylate (311-3).

To a solution of methyl(2S,3R)-3-((methoxycarbonyl)amino)piperidine-2-carboxylate (311-3) (30g, about 105 mmol, 1.0 eq) in THF (300 mL) was added TEA (53 g, 525mmol, 5.0 eq) and Boc₂O (69 g, 315 mmol, 3.0 eq) at 20° C. for 18 h. Thereaction mixture was concentrated and diluted with water (100 mL),acidified with 1 N HCl to PH=3, extracted with EA (100 mL×3), washedwith brine (100 mL), dried over Na₂SO₄, concentrated. The residue waspurified by combi-flash (EA %=0%-50%) to give 1-(tert-butyl) 2-methyl(2S,3R)-3-((methoxycarbonyl)amino)piperidine-1,2-dicarboxylate (311-4).

To a solution of 1-(tert-butyl) 2-methyl(2S,3R)-3-((methoxycarbonyl)amino)piperidine-1,2-dicarboxylate (311-4)(33 g, 104 mmol, 1.0 eq) in anhydrous THF (660 mL) was added LiAlH₄(5.15 g, 136 mmol, 1.3 eq) at −78° C.˜−10° C. for 2 h. The reactionmixture was poured into sat.NH₄Cl (700 mL), acidified with 1 N HCl toPH=5, extracted with EA (500 mL×3), washed with brine (500 mL), driedover Na₂SO₄, concentrated. The residue was purified by combi-flash (EA%=0%-70%) to give tert-butyl(2S,3R)-2-(hydroxymethyl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(311-5). ¹H NMR (400 MHz, CDCl₃) δ: 5.70 (br s, 1H), 4.44 (br d, J=5.5Hz, 1H), 3.92 (br d, J=10.9 Hz, 2H), 3.86-3.71 (m, 2H), 3.64 (br s, 3H),2.98-2.64 (m, 2H), 1.92-1.80 (m, 1H), 1.73-1.63 (m, 1H), 1.61-1.50 (m,2H), 1.44 (s, 9H). LC-MS: [M+H]⁺=289.2.

To a mixture of tert-butyl(2S,3R)-2-(hydroxymethyl)-3-((methoxycarbonyl)amino)piperidine-1-carboxylate(311-5) (5 g, 17 mmol, 1.0 eq), BnBr (12 g, 69 mmol, 1.0 eq) and TBAI(3.1 g, 9 mmol, 0.5 eq) in anhydrous THF (50 mL) was added NaH (2.6 g,65 mmol, 3.8 eq) at 20° C. After the addition, the reaction was stirredat 60° C. for 2 h. The reaction mixture was poured into a solution ofsat.NH₄Cl (200 mL), extracted with EA (100 mL×3), washed with brine (50mL), dried over Na₂SO₄, concentrated. The residue was purified bycombi-flash (EA %=0%-50%) to give tert-butyl(2S,3R)-3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidine-1-carboxylate(311-6). ¹H NMR (400 MHz, CDCl₃) δ: 7.53-6.90 (m, 10H), 4.90-3.31 (m,12H), 3.08-2.74 (m, 1H), 1.97-1.79 (m, 1H), 1.62-1.50 (m, 1H), 1.50-1.42(m, 1H), 1.41-1.28 (m, 9H). LC-MS: [M+H]⁺=469.4.

A solution of tert-butyl(2S,3R)-3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidine-1-carboxylate(intermediate 311-6) (7.2 g, 15 mmol, 1.0 eq) in DCM (40 mL) and TFA (20mL) was stirred at 20° C. for 20 h. The reaction mixture was dilutedwith H₂O (100 mL), basified with K₂CO₃(s) to PH=9, extracted with EA(100 mL×3), washed with brine, dried over Na₂SO₄, concentrated to givemethyl benzyl((2S,3R)-2-((benzyloxy)methyl)piperidin-3-yl)carbamate(311-7). LC-MS: [M+H]+=369.5.

A mixture of methyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate(Intermediate A) (30 g, 0.112 mmol, 1.0 eq) and m-CPBA (30 g, 0.174mmol, 1.55 eq) in CDCl₃ (500 mL) was stirred at 65° C. for 20 h. Morem-CPBA (30 g, 0.174 mmol, 1.55 eq) was added to the reaction mixture andthe reaction was stirred at 65° C. for 72 h. The reaction mixture wasdiluted with water (300 mL), basified with K₂CO₃(s) to PH=8, extractedwith EA (300 mL×3), washed with brine (300 mL, dried over Na₂SO₄, andconcentrated. The crude was purified by trituration with PE/MTBE=1/1(100 mL) to give2-(3,4-difluorophenyl)-5-fluoro-4-(methoxycarbonyl)pyridine 1-oxide(311-7A). LC-MS: [M+H]⁺=284.2.

To a mixture of methylbenzyl((2S,3R)-2-((benzyloxy)methyl)piperidin-3-yl)carbamate (311-7) (17g, 0.06 mol, 4.0 eq) and2-(3,4-difluorophenyl)-5-fluoro-4-(methoxycarbonyl)pyridine 1-oxide(311-7A) (6 g, about 15 mmol, 1.0 eq) in DIPEA (40 mL) and DMSO (40 mL)was stirred at 120° C. for 5 h. The reaction mixture was diluted withH₂O (100 mL), extracted with EA (50 mL×3), washed with brine (20 mL),dried over Na₂SO₄, concentrated. The residue was purified by combi-flash(EA %=10%-100%) to give5-(3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)-4-(methoxycarbonyl)pyridine1-oxide (311-8). LCMS: [M+H]⁺=632.5.

To a mixture of5-(3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)-4-(methoxycarbonyl)pyridine1-oxide (311-8) (5200 mg, about 4.69 mmol, 1.0 eq) and Pd(OH)₂ (2000 mg,38% wt) in MeOH (25 mL) and EA (25 mL) was stirred at 60° C. and 50 Psifor 20 h. The reaction mixture was filtered and concentrated. Theresidue was purified by combi-flash (EA %=0%-60%) to give methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate (311-9). LCMS:[M+H]+=616.7.

To a mixture of methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-((benzyloxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(311-9) (1500 mg, 2.44 mmol, 1.0 eq) and Pd(OH)₂ (1500 mg, 100% wt) inEA (45 mL) was stirred at 60° C. and 50 Psi for 18 h. The reactionmixture was filtered and concentrated. The residue was purified bycombi-flash (EA %=0%-50%) to give methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-(hydroxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(311-10). LCMS: [M+H]⁺=526.5.

To a solution of methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-(hydroxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(311-10) (300 mg, 0.571 mmol) and CuI (21.74 mg, 0.114 mmol) in MeCN (10mL), was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.113 mL,1.142 mmol) dropwise at 55° C., the reaction mixture was stirred at 55°C. for 2 hr. The reaction mixture was diluted with EA, washed with waterand brine. The organic layer was dried over Na₂SO₄ and concentratedunder vacuum to give the crude product. The crude product was purifiedby flash chromatography (elution gradient:0% to 40% EtOAc in PE in 30mins) to give methyl5-(3-(benzyl(methoxycarbonyl)amino)-2-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(Intermediate 311-11). LCMS: [M+H]⁺=576.3.

EXAMPLES Example 1:(R)-9-((5-(3-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine

A suspension of 5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinaldehyde(intermediate 1-1) (800 mg, 3.21 mmol), (R)-tert-butylpiperidin-3-ylcarbamate (643 mg, 3.21 mmol), and potassium carbonate(887 mg, 6.42 mmol) in DMF (15 mL) was stirred at 100° C. for 20 hr. Themixture was diluted with H₂O (30 mL), extracted with EtOAc (20 mL*3).The combined organic layers were washed with H₂O (20 mL*2), brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (0-30%EtOAc in PE in 30 mins) to give tert-butyl(R)-(1-(6-(3-fluoro-4-methoxyphenyl)-4-formylpyridin-3-yl)piperidin-3-yl)carbamate(1-2). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.63 (s, 1H), 8.01 (s,1H), 7.93-7.83 (m, 2H), 7.27 (t, J=8.8 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H),3.90 (s, 3H), 3.63 (s, 1H), 3.42-3.37 (m, 1H), 3.30-3.23 (m, 1H),3.06-2.94 (m, 1H), 2.84 (dd, J=11.7, 9.0 Hz, 1H), 1.85 (d, J=11.2 Hz,2H), 1.70 (d, J=10.5 Hz, 1H), 1.40 (s, 10H). LC-MS: [M+H]⁺=429.9.

To a suspension of tert-butyl(R)-(1-(6-(3-fluoro-4-methoxyphenyl)-4-formylpyridin-3-yl)piperidin-3-yl)carbamate(1-2) (260 mg, 0.605 mmol) in MeOH (15 mL) was added sodium borohydride(22.9 mg, 0.605 mmol). The mixture was stirred at RT for 30 min and thesolvent removed in reduced pressure. The residue was redissolved in DCM(30 mL), worked up under aqueous conditions and concentrated. Theresidue was purified by flash chromatography (10-50% EtOAc in PE in 30mins) to afford tert-butyl(R)-(1-(6-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(1-3). ¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 7.93 (s, 1H), 7.75-7.62(m, 2H), 7.21 (t, J=8.5 Hz, 1H), 5.52 (s, 1H), 4.88-4.72 (m, 2H), 3.95(s, 3H), 3.71 (dt, J=9.5, 4.8 Hz, 1H), 3.21 (dd, J=11.2, 3.7 Hz, 1H),3.07 (d, J=11.6 Hz, 1H), 2.83 (t, J=10.7 Hz, 1H), 2.66 (t, J=10.0 Hz,1H), 2.06-1.86 (m, 2H), 1.78 (q, J=13.1, 11.6 Hz, 1H), 1.47 (s, 9H).LC-MS: [M+H]⁺=431.9.

To a solution of tert-butyl(R)-(1-(6-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(1-3) (370 mg, 0.857 mmol), Intermediate B (300 mg, 0.895 mmol) and PPh₃(704 mg, 2.68 mmol) in THF (15 mL) was added DEAD (0.425 mL, 2.68 mmol)dropwise at 0° C., The mixture was stirred at rt for 1 hr. The mixturewas diluted with H₂O (20 mL), extracted with EtOAc (20 mL*3). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (10-50% EtOAc in hexane in40 mins) to give tert-butyl(R)-(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(1-4). ¹H NMR (400 MHz, CD₃OD) b 8.88 (s, 1H), 8.76 (s, 1H), 8.45 (s,1H), 7.54-7.44 (m, 2H), 7.26 (s, 1H), 7.13 (t, J=8.6 Hz, 1H), 5.90-5.72(m, 2H), 3.90 (s, 3H), 3.85 (d, J=4.6 Hz, 1H), 3.42-3.37 (m, 1H),3.18-3.09 (m, 1H), 2.99 (t, J=10.1 Hz, 1H), 2.88 (d, J=10.1 Hz, 1H),1.97 (d, J=10.2 Hz, 2H), 1.82 (d, J=6.8 Hz, 1H), 1.64-1.54 (m, 1H), 1.44(s, 9H), 1.36 (s, 18H). LC-MS: [M+H]⁺=749.0.

To a solution of tert-butyl(R)-(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(1-4) (360 mg, 0.481 mmol) in DCM (9 mL) was added TFA (3 mL). Themixture was stirred at RT for 1 hr. The mixture was concentrated invacuum. The residue was purified by Prep-HPLC (Basic condition, NH₃H₂O%=0.05%, MECN/H₂O=0-95% in 12 mins) to give(R)-9-((5-(3-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine(Example 1). ¹H NMR (400 MHz, CD₃OD) δ 8.59-8.32 (m, 3H), 7.69-7.53 (m,2H), 7.37 (s, 1H), 7.17 (td, J=8.6, 1.7 Hz, 1H), 5.85-5.63 (m, 2H), 3.93(d, J=1.8 Hz, 3H), 3.62 (s, 1H), 3.56-3.44 (m, 1H), 3.19-3.07 (m, 2H),3.04 (d, J=9.5 Hz, 1H), 2.22-2.12 (m, 1H), 2.04 (s, 1H), 1.89 (dd,J=9.0, 4.2 Hz, 1H), 1.76 (d, J=10.1 Hz, 1H). LC-MS: [M+H]⁺=449.1.

Example 2-21 can be prepared following procedures analogous to thosedescribed in Example 1.

Example # Structure ¹H NMR & MS 2

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1 H) 8.26 (s, 1 H) 8.11 (s, 1 H)7.85 (td, J = 8.03, 1.76 Hz, 1 H) 7.35-7.43 (m, 1 H) 7.32 (s, 2 H)7.17-7.29 (m, 2 H) 6.97 (s, 1 H) 5.42-5.68 (m, 2 H) 4.66- 4.94 (m, 1 H)2.86-3.19 (m, 4 H) 1.87-2.23 (m, 2 H) 1.73 (b,. s., 1 H), LC-MS: [M +H]+ = 436.9, 437.9. 3

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.22 (d, J = 4.7 Hz, 2H),7.73 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.52 (ddt, J = 8.2, 3.8, 1.6 Hz,1H), 7.28 (d, J = 11.2 Hz, 2H), 5.63 (d, J = 1.4 Hz, 2H), 3.90 (dt, J =7.4, 3.5 Hz, 1H), 3.25-2.98 (m, 4H), 2.89 (ddd, J = 11.5, 7.4, 3.8 Hz,1H), 1.90 (dddd, J = 33.5, 13.2, 6.7, 3.6 Hz, 2H), LC-MS: [M + H]⁺ =453.2, 454.2. 4

¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J = 6.2 Hz, 1H), 8.47 (d, J = 6.0 Hz,1H), 8.37 (d, J = 5.8 Hz, 1H), 7.68-7.56 (m, 2H), 7.50-7.39 (m, 2H),7.15 (td, J = 8.2, 7.7, 2.3 Hz, 1H), 5.85-5.67 (m, 2H), 3.62 (tt, J =8.1, 3.7 Hz, 1H), 3.51 (dd, J = 11.4, 3.7 Hz, 1H), 3.14 (dq, J = 10.5,6.5, 4 5 Hz, 2H), 3.05 (td, J = 8.5, 4.2 Hz, 1H), 2.24-2.11 (m, 1H),2.05 (dtt, J = 9.5, 6.1, 3.1 Hz, 1H), 1.90 (ddq, J = 13.2, 8.8, 4.0 Hz,1H), 1.82-1.69 (m, 1H), LC-MS: [M + H]⁺ = 418.9. 5

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.24 (d, J = 1.5 Hz, 2H),7.58 (dd, J = 12.6, 2.2 Hz, 1H), 7.48 (ddd, J = 8.5, 2.3, 1.2 Hz, 1H),7.25 (s, 1H), 7.13 (t, J = 8.6 Hz, 1H), 5.64 (s, 2H), 4.79 (dd, J = 5.4,2.6 Hz, 1H), 3.91 (s, 3H), 3.22-3.02 (m, 4H), 3.02- 2.88 (m, 1H), 2.20(ddd, J = 15.0, 9.6, 4.9 Hz, 1H), 2.03 (ddd, J = 36.1, 14.0, 10.3 Hz,1H), LC-MS: [M + H]⁺ = 466.9, 467.9. 6

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 7.71(t, J = 9.0 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 6.86 (dd, J = 8.8, 2.5Hz, 1H), 6.75 (dd, J = 13.3, 2.5 Hz, 1H), 5.84-5.67 (m, 2H), 3.84 (s,3H), 3.63 (dt, J = 8.3, 4.5 Hz, 1H), 3.55-3.48 (m, 1H), 3.19- 3.11 (m,2H), 3.05 (t, J = 8.8 Hz, 1H), 2.23-2.13 (m, 1H), 2.11-2.02 (m, 1H),1.91 (ddq, J = 13.2, 8.6, 4.3 Hz, 1H), 1.77 (d, J = 9.2 Hz, 1H), LC-MS:[M + H]⁺ = 448.9. 7

1H NMR (400 MHz, CDCl₃): 8.61 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 8.17(d, J = 1.8 Hz, 1H), 7.92 (dd, J = 8.3, 1.7 Hz, 1H), 7.81 (d, J = 8.1Hz, 1H), 7.50 (s, 1H), 5.92-5.49 (m, 2H), 3.60 (tt, J = 7.7, 3.5 Hz,1H), 3.50 (dd, J = 11.5, 3.4 Hz, 1H), 3.23-2.97 (m, 3H), 2.09 (dddd, J =41.4, 10.0, 7.1, 3.5 Hz, 2H), 1.92-1.62 (m, 2H) LC-MS: [M + H]+ = 459.88

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.24 (d, J = 3.3 Hz, 2H),7.60-7.50 (m, 2H), 7.43 (td, J = 8.3, 6.1 Hz, 1H), 7.31 (s, 1H), 7.12(tt, J = 7.7, 1.5 Hz, 1H), 5.66 (s, 2H), 4.80-4.57 (m, 1H), 3.25-3.06(m, 4H), 3.06-2.91 (m, 1H), 2.21 (td, J = 11.0, 10.3, 5.7 Hz, 1H), 2.04(ddd, J = 36.2, 14.1, 10.4 Hz, 1H). LC-MS: [M + H]+ = 436.9, 437.9. 9

¹H NMR (400 MHz, CD₃OD) δ ppm 8.80 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H),8.07 (dd, J = 10.8, 1.5 Hz, 1H), 8.01 (dd, J = 8.2,1.6 Hz, 1H), 7.96 (s,1H), 7.88 (dd, J = 8.2, 6.7 Hz, 1H), 6.03 (d, J = 15.3 Hz, 1H), 5.43 (d,J = 15.3 Hz, 1H), 3.88 (d, J = 4.0 Hz, 1H), 3.64-3.50 (m, 2H), 3.42-3.34(m, 1H), 3.16 (s, 3H), 3.11-2.95 (m, 2H), 2.15-1.97 (m, 2H), 1.69-1.57(m, 1H), 1.57-1.39 (m, 1H). LC-MS: [M + H]+ = 487.9, 488.9. 10

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H),7.81 (t, J = 9.3 Hz, 1H), 7.32 (s, 2H), 6.91-6.71 (m, 3H), 5.54 (s, 2H),4.81 (ddt, J = 49.4, 5.4, 2.5 Hz, 1H), 3.77 (s, 3H), 3.18- 2.83 (m, 5H),2.20-1.88 (m, 2H), 1.85-1.58 (m, 2H). LC-MS: [M + H]+ = 466.9, 470.9. 11

¹H NMR (400 MHz, CD₃OD) δ: 8.50 (d, J = 26.4 Hz, 2H), 8.36 (s, 1H), 7.73(d, J = 8.9 Hz, 2H), 7.40 (s, 1H), 7.14-6.93 (m, 2H), 5.93-5.62 (m, 2H),3.85 (s, 3H), 3.57 (ddd, J = 44.7, 9.9, 3.8 Hz, 2H), 3.22- 3.01 (m, 3H),2.22-1.99 (m, 2H), 1.94-1.69 (m, 2H). LC-MS: [M + H]+ = 430.9 12

¹H NMR (400 MHz, CD₃OD) δ ppm 8.57 (d, J = 2.3 Hz, 1H), 8.32-8.17 (m,2H), 7.87 (p, J = 1.6 Hz, 1H), 7.67 (ddt, J = 5.1, 3.2, 1.8 Hz, 1H),7.47-7.30 (m, 3H), 5.65 (s, 2H), 5.15-4.95 (m, 1H), 3.63 (dd, J = 39.0,22.1 Hz, 1H), 3.38 (d, J = 6.0 Hz, 1H), 3.26 (s, 1H), 3.22-3.13 (m, 1H),3.04 (dq, J = 12.6, 4.5 Hz, 1H), 2.32-2.04 (m, 2H), LC-MS: [M + H]+ =452.9, 453.9. 13

¹H NMR (400 MHz, CD₃OD) δ ppm 8.6 (s, 1H), 8.23 (d, 2H), 7.9 (d, 1H),7.79 (m, 2H), 7.45 (s, 1H), 5.6 (s, 2H), 4.9 4.81 (m, 1H), 3.83 (s, 3H),3.21-3.12 (m, 4H), 3.05-3.01 (m, 1H), 2.19 (m, 1H), 2.14- 1.88 (m, 1H),LC-MS: [M + H]+ = 461.9, 462.9. 14

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.23 (d, J = 1.3 Hz, 2H),7.61 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 (s, 1H),6.76 (d, J = 8.4 Hz, 1H), 5.64 (s, 2H), 4.65 (s, 1H), 4.58 (t, J = 8.7Hz, 2H), 3.23 (t, J = 8.7 Hz, 2H), 3.20-3.04 (m, 4H), 3.00-2.92 (m, 1H),2.26-2.13 (m, 1H), 2.12-1.93 (m, 1H), LC-MS: [M + H]+ = 460.9, 461.9. 15

¹H NMR (400 MHz, CD₃OD) δ ppm 8.44 (s, 1H), 8.23 (d, J = 1.3 Hz, 2H),7.56 (dd, J = 12.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.5, 2.3, 1.1 Hz, 1H),7.24 (s, 1H), 7.09 (t, J = 8.7 Hz, 1H), 5.62 (s, 2H), 3.48 (dt, J = 7.1,3.3 Hz, 1H), 3.44 (s, 3H), 3.22-2.95 (m, 4H), 2.85 (ddd, J = 11.4, 7.4,3.6 Hz, 1H), 2.06 (ddt, J = 18.0, 7.4, 3.0 Hz, 1H), 1.87-1.73 (m, 1H),LC- MS: [M + H]+ = 478.9, 479.9. 16

¹H NMR (400 MHz, DMSO-d₆) δ: 8.52 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H),7.67 (dd, J = 13.0, 2.1 Hz, 1H), 7.52 (s, 1H), 7.31 (s, 1H), 7.27-7.07(m, 2H), 5.50 (d, J = 2.7 Hz, 2H), 3.85 (s, 3H), 3.32-3.09 (m, 3H), 2.71(t, J = 10.2 Hz, 1H), 2.36 (d, J = 12.1 Hz, 1H), 2.09-1.54 (m, 3H), 1.06(t, J = 7.0 Hz, 1H) LC-MS: [M + H]+ = 485.1 17

¹H NMR (400 MHz, CD₃OD) δ: 8.64 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H),7.67-7.55 (m, 2H), 7.52-7.35 (m, 2H), 7.22-7.02 (m, 1H), 5.87-5.64 (m,2H), 4.10 (ddt, J = 18.1, 9.6, 4.6 Hz, 1H), 3.63 (d, J = 11.8 Hz, 1H),3.46-3.37 (m, 1H), 3.32-3.26 (m, 2H), 2.57-2.37 (m, 2H) LC-MS: [M + H]+= 454.9 18

¹H NMR (400 MHz, DMSO-d₆): d 8.51 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H),7.95-7.85 (m, 1H), 7.67-7.57 (m, 1H), 7.49 (q, J = 8.8 Hz, 1H), 7.38 (s,1H), 7.28 (s, 2H), 5.49 (s, 2H), 3.27-3.15 (m, 1H), 3.14-3.05 (m, 1H),3.04-2.97 (m, 1H), 2.86-2.77 (m, 1H), 2.70-2.55 (m, 2H), 2.20-2.02 (m,3H), 1.95-1.80 (m, 1H). LC-MS: [M + H]+ = 462.3 19

¹H NMR (400 MHz, CD₃OD) δ: 8.54 (s, 1H), 8.48 (s, 1H), 7.79-7.45 (m,3H), 7.23 (s, 1H), 7.14 (t, J = 8.6 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H),5.92-5.61 (m, 2H), 3.91 (s, 3H), 3.62-3.51 (m, 1H), 3.47 (dd, J = 11.4,3.5 Hz, 1H), 3.12 (dq, J = 14.0, 4.9, 4.0 Hz, 2H), 3.04-2.94 (m, 1H),2.17 (dt, J = 10.4, 5.0 Hz, 1H), 2.10-1.98 (m, 1H), 1.97-1.81 (m, 1H),1.72 (d, J = 10.5 Hz, 1H) LC-MS: [M + H]+ = 447.8 20

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.61(dd, J = 12.6, 2.2 Hz, 1H), 7.55 (dt, J = 8.8, 1.6 Hz, 1H), 7.28 (s,1H), 7.14 (t, J = 8.6 Hz, 1H), 5.76 (q, J = 16.4 Hz, 2H), 3.91 (s, 3H),3.26 (s, 2H), 3.20-3.13 (m, 1H), 2.96 (t, J = 10.9 Hz, 1H), 1.98 (t, J =10.9 Hz, 3H), 1.89-1.80 (m, 1H), 1.52 (s, 3H). LC-MS: [M + H]⁺ = 462.9.21

¹H NMR (400 MHz, CD₃OD) δ: 8.54 (s, 1H), 8.48 (s, 1H), 7.66-7.41 (m,3H), 7.23 (s, 1H), 7.14 (t, J = 8.6 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H),5.89-5.68 (m, 2H), 3 91 (s, 3H), 3.58 (tt, J = 8.3, 4.0 Hz, 1H), 3.47(dd, J = 11.3, 3.5 Hz, 1H), 3.20-3.08 (m, 2H), 3 04 (d, J = 3.2 Hz, 1H),2.17 (dt, J = 10.4, 5.0 Hz, 1H), 2.10-1.99 (m, 1H), 1.90 (qt, J = 9.4,4.2 Hz, 1H), 1.80-1.62 (m, 1H). LC-MS: [M + H]+ = 447.8

Example 22:(R)-9-((5-(3-amino-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine

A mixture of tert-butyl (3-(cyclopropoxymethyl)piperidin-3-yl)carbamate(Intermediate 22-7) (300 mg, 1.11 mmol, 1.0 eq), methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate (intermediate A) (296 mg,1.11 mmol, 1.0 eq) and DIPEA (1.00 g, 7.77 mmol, 7.0 eq) in DMSO (3 mL)was stirred at 120° C. under N₂ for 3 hr. The mixture was quenched withwater (200 mL) at 10° C., and extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by Combi Flash (20%EtOAc in PE) to give methyl5-(3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(22-8). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.48 (1H, s), 7.86 (1H, s), 7.83(1H, dd, J=10.0, 2.0 Hz), 7.67 (1H, d, J=8.4 Hz), 7.23 (1H, dd, J=8.4,1.6 Hz), 5.63 (1H, brs), 3.80-4.05 (4H, m), 3.57 (1H, d, J=9.6 Hz),3.15-3.35 (3H, m), 2.80-2.95 (2H, m), 2.30-2.45 (1H, m), 1.85-2.00 (1H,m), 1.65-1.75 (1H, m), 1.46 (9H, s), 1.25-1.40 (1H, m), 0.40-0.60 (4H,m).

To a solution of methyl5-(3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(22-8) (330 mg, 0.638 mmol, 1.0 eq) in THF/MeOH (10 mL, v/v=1/1) wasadded LiCl (270 mg, 6.38 mmol, 10.0 eq) followed by NaBH₄ (480 mg, 12.75mmol, 20.0 eq) at 15-20° C. The resulting mixture was stirred at 30° C.for 2 hr. The reaction was quenched with water (100 mL), and extractedwith EtOAc (100 mL×3). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated in vacuo to give crude tert-butyl(3-(cyclopropoxymethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(22-9). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.43 (1H, s), 7.75-7.85 (1H, m),7.60-7.70 (2H, m), 7.15-7.25 (1H, m), 4.79 (2H, s), 4.76 (1H, brs),3.65-3.85 (3H, m), 3.35-3.45 (1H, m), 3.25-3.35 (1H, m), 3.05-3.15 (1H,m), 2.80-2.95 (2H, m), 2.05-2.15 (1H, m), 1.85-1.95 (1H, m), 1.65-1.75(1H, m), 1.55-1.60 (1H, m), 1.44 (9H, s), 0.40-0.60 (4H, m).

To a solution of tert-butyl(3-(cyclopropoxymethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(22-9) (300 mg, 0.613 mmol, 1.0 eq.), Intermediate B (310 mg, 0.919mmol, 1.5 eq.) and Bu₃P (372 mg, 1.84 mmol, 3.0 eq.) in THF (10 mL) wasadded DIAD (372 mg, 1.84 mmol, 3.0 eq.) at 0° C. The mixture was stirredat 20-30° C. for 2 hr. The reaction was concentrated in vacuo. Theresidue was purified by Combi Flash (30-40% EtOAc in PE) to givetert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(22-10). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.88 (1H, s), 8.52 (1H, s), 8.25(1H, s), 7.60-7.70 (1H, m), 7.35-7.45 (1H, m), 7.10-7.25 (2H, m), 5.70(1H, d, J=15.6 Hz), 5.53 (1H, d, J=15.6 Hz), 5.19 (1H, brs), 3.75-3.90(2H, m), 3.40-3 intermediate. 50 (1H, m), 3.25-3.35 (1H, m), 2.90-3.10(3H, m), 2.15-2.30 (1H, m), 1.90-2.00 (1H, m), 1.70-1.80 (1H, m),1.55-1.65 (1H, m), 1.45 (18H, s), 1.35 (9H, s), 0.40-0.60 (4H, m).

A solution of tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(22-10) (270 mg, 0.335 mmol) in 20% TFA in DCM (7.5 mL) was stirred at15-20° C. for 2 hr. Then the pH of the reaction was adjusted to 8-9 byNH₃.H₂O, and extracted with DCM (100 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by Prep-HPLC (0.1% NH₃.H₂O as additive) and SFC to give(R)-9-((5-(3-amino-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine(Example 22). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (1H, s), 8.25 (1H, d,J=4.0 Hz), 7.70-7.80 (1H, m), 7.50-7.60 (1H, m), 7.25-7.40 (2H, m), 5.66(2H, s), 3.60-3.80 (1H, m), 3.45-3.55 (1H, d, J=9.6 Hz), 2.90-3.15 (4H,m), 1.55-2.00 (4H, m), 1.25-1.40 (1H, m), 0.35-0.65 (4H, m). LC-MS:[M+H]⁺=506.8.

Example 23-46 can be prepared following procedures analogous to thosedescribed in Example 22.

Example # Structure ¹H NMR & MS 23

¹H NMR (400 MHz, CDCl₃) δ ppm 8.50 (s, 1H), 8.36 (br s, 1H), 8.16 (br s,1H), 7.76-7.91 (m, 2H), 7.65 (br d, J = 7.0 Hz, 1H), 7.20-7.27 (m, 1H),5.71 (br d, J = 12.8 Hz, 1H), 5.47 (brs, 1H), 3.58-3.70 (m, 2H), 3.54(br d, J = 12.0 Hz, 1H), 3.45 (s, 3H), 2.93-3.06 (m, 1H), 2.86 (br s,2H), 2.28 (br d, J = 14.3 Hz, 1H), 2.05 (brs, 1H), 1.75 (br d, J = 13.8Hz, 1H), 1.56-1.68 (m, 1H), 1.18- 1.39 (m, 3H), 0.80-0.95 (m, 1H),LC-MS: [M + H]⁺ = 480.9. 24

¹H NMR (400 MHz, CD₃OD) δ ppm 1.40-1.82 (4H, m), 2.68-3.05 (4H, m), 3.20(1H, t), 3.26 (3H, s), 3.42 (1H, d), 5.56 (3H, t), 7.01 (1H, t), 7.15(1H, s), 7.25-7.44 (2H, m), 8.12 (2H, d), 8.38 (1H, s), LC-MS: [M + H]⁺= 463.1. 25

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.24 (d, J = 6.4 Hz, 2H),7.56 (dd, J = 12.8, 2.2 Hz, 1H), 7.45 (dt, J = 8.6, 1.6 Hz, 1H), 7.18(s, 1H), 7.11 (t, J = 8 6 Hz, 1H), 5.67 (s, 2H), 3.90 (s, 3H), 3.74-3.53(m, 2H), 3.14 (d, J- 11.3 Hz, 1H), 3.10- 2.93 (m, 2H), 2.87 (d, J = 11.4Hz, 1H), 2.00-1.74 (m, 2H), 1.73-1.48 (m, 2H), 1.17 (d, J = 6.0 Hz, 3H),1.12 (d, J = 6.1 Hz, 3H), LC-MS: [M + H]⁺ = 520.8, 521.8. 26

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1H), 8.29 (s, 1H), 8.11 (s,1H), 7.88 (dd, J = 6.8, 2.8 Hz, 1H), 7.45 (ddd, J = 8.7, 4.1, 2.8 Hz,1H), 7.40-7.22 (m, 3H), 7.00 (d, J = 1.5 Hz, 1H), 5.63- 5.47 (m, 2H),3.46 (d, J = 8.8 Hz, 1H), 3.28 (s, 3H), 3.23 (d, J = 8.8 Hz, 1H),3.08-2.93 (m, 3H), 2.75 (d, J = 11.3 Hz, 1H), 1.88 (d, J = 13.0 Hz, 1H),1.72 (s, 3H), 1.61 (td, J = 8.7, 4.5 Hz, 1H), 1.40 (dt, J = 12.6, 5.2Hz, 1H). LC-MS: [M + H]⁺ = 496.8, 497.8. 27

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.50 (s, 1H), 8.33 (s, 1H), 8.13 (s,1H), 7.89 (t, J = 1.9 Hz, 1H), 7.71 (dt, J = 7.2, 1.8 Hz, 1H), 7.51-7.38 (m, 2H), 7.32 (d, J = 13.0 Hz, 3H), 5.61- 5.42 (m, 2H), 3.41 (d, J= 8.8 Hz, 1H), 3.26 (s, 3H), 3.21 (d, J = 8.8 Hz, 1H), 3.04-2.86 (m,3H), 2.73 (d, J = 11.2 Hz, 1H), 1.92-1.52 (m, 5H), 1.37 (ddt, J = 10.6,8.0, 3.9 Hz, 1H). LC-MS: [M + H]⁺ = 478.9, 479.9. 28

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.22-8.27 (m, 2H), 7.96 (d,J = 6.7 Hz, 1H), 7.64- 7.71 (m, 2H), 7.28 (s, 1H), 5.67 (s, 2H), 3.57(br d, J = 9.3 Hz, 1H), 3.36-3.39 (m, 4H), 3.04-3.16 (m, 2H), 2.86-3.04(m, 2H), 1.75-1.93 (m, 2H), 1.50-1.73 (m, 2H). LC-MS: [M + H]⁺ = 496.8.29

¹H NMR (400 MHz, CDCl₃) δ ppm 8.55 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H),7.88 (td, J = 8.8, 6.7 Hz, 1H), 6.96 (td, J = 8.3, 2.0 Hz, 1H), 6.84(ddd, J = 11.3, 8.8, 2.5 Hz, 1H), 5.48-5.65 (m, 2H), 3.53-3.61 (m, 1H),3.38 (s, 3H), 3.29-3.35 (m, 1H), 2.91-3.09 (m, 4H), 1.88-2.01 (m, 2H),1.63 (br s, 2H). LC-MS: [M + H]⁺ = 480.9. 30

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.24 (s, 1H), 8.24 (s, 1H),7.78-7.72 (m, 1H), 7.54-7.52 (m, 2H), 7.33-7.26 (m, 2H), 5.67 (s, 1H),3.98-3.94 (m, 1H), 3.56-3.54 (m, 1H), 3.32 (d, J = 6 Hz, 1H), 3.12-2.94(m, 3H), 1.93- 1.50 (m, 8H). LC-MS: [M + H]⁺ = 520.7. 31

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (1H, s), 8.31 (1H, s), 8.12 (1H,s), 7.66 (1H, dd, J = 13.2, 2.0 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.30 (2H,brs), 7.15-7.25 (2H, m), 5.45-5.60 (2H, m), 3.84 (3H, s), 3.53 (1H, d, J= 8.8 Hz), 3.20-3.35 (2H, m), 2.85- 2.95 (3H, m), 2.68 (1H, d, J = 11.2Hz), 1.25-1.85 (6H, m), 0.25-0 50 (4H, m). LC-MS: [M + H]⁺ = 519.1. 32

¹H NMR (400 MHz, CD₃OD) δ ppm 8.33 (s, 1H), 8.13 (s, 1H), 8.12 (s, 1H),7.43 (dd, J = 2.0, 12.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H),7.00-6.97 (m, 1H), 5.59-5.50 (m, 2H), 3.86-3.79 (m, 1H), 3.77 (s, 3H),3.44 (d, J = 8.0 Hz, 1H), 3.12 (d, J = 8.8 Hz), 3.04-3.01 (m, 1H),2.95-2.86 (m, 2H), 2.75-2.72 (m, 1H), 2.09-2.00 (m, 2H), 1.84- 1.74 (m,3H), 1.68-1.16 (m, 5H) LC-MS: [M + H]⁺ = 533.2. 33

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.48 (s, 1H), 8.29 (s, 1H), 8.11 (s,1H), 7.80 (t, J = 9.3 Hz, 1H), 7.32 (s, 2H), 6.90-6.75 (m, 3H), 5.61-5.43 (m, 2H), 3.77 (s, 3H), 3.47 (d, J = 8.8 Hz, 1H), 3.28 (s, 3H), 3.24(d, J = 8.8 Hz, 1H), 2.98 (t, J = 11.8 Hz, 3H), 2.75-2.66 (m, 1H),1.94-1.77 (m, 1H), 1.72 (s, 3H), 1.60 (ddd, J = 13.0, 8.6, 4.3 Hz, 1H),1.39 (ddd, J = 12.3, 7.4, 4.4 Hz, 1H). LC-MS: [M + H]⁺ = 492.9, 493.9.34

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (s, 1H), 8.31 (s, 1H), 8.12 (s,1H), 7.87 (ddd, J = 12.2, 8.0, 2.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H),7.48 (dt, J = 10.8, 8.5 Hz, 1H), 7.29 (d, J = 5.8 Hz, 3H), 5.64-5.38 (m,2H), 3.60-3.41 (m, 2H), 3.21 (d, J = 8.8 Hz, 1H), 3.08-2.85 (m, 3H),2.70 (d, J = 11.5 Hz, 1H), 1.83 (s, 1H), 1.68 (s, 3H), 1.58 (ddd, J =13.0, 8.7, 4.2 Hz, 1H), 1.46-1.31 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H),1.02 (d, J = 6.0 Hz, 3H). LC-MS: [M + H]⁺ = 508.9, 509.9. 35

¹H NMR (400 MHz, CD₃OD) δ ppm 1.73-2.05 (7H, m), 2.84-2.90 (1H, m),3.03-3.07 (2H, m), 3.84 (3H, s), 3.88 (3H,s), 5.49-5.59 (2H, m), 7.01(1H, t, J = 8.4 Hz), 7.21 (1H, s), 7.38 (1H, d, J = 8.4 Hz), 7.48 (1H,dd, J = 8.8 Hz, 2.4 Hz), 8.14 (1H, d, J = 7.2 Hz), 8.38 (1H, s), LC-MS:[M + H]⁺ = 503.3. 36

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.25 (s, 1H), 8.24 (s, 1H),7.19 (s, 1H), 7.15 (t, J = 6.8 Hz, 2H), 5.69 (dd, J1 = 13.2 Hz, J2 =15.2 Hz, 2H), 4.00-3.91 (m, 1H), 3.58 (br, 1H), 3.25 (d, J = 7.2 Hz,1H), 3.22-3.15 (m, 1H), 3.13- 2.97 (m, 2H), 2.93-2.83 (m, 1H), 2.26-2.17(m, 1H), 2.16-2.07 (m, 1H), 1.97-1.75 (m, 4H), 1.72-1.45 (m, 4H). LC-MS:[M + H]⁺ = 503.2. 37

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.25 (d, J = 7.2 Hz, 2H),7.86-7.70 (m, 2H), 7.25 (s, 1H), 7.21-7.08 (m, 2H), 5.68 (s, 2H),3.78-3.55 (m, 2H), 3.41 (d, J = 9.3 Hz, 1H), 3.24-3.15 (m, 1H),3.11-2.86 (m, 3H), 2.01- 1.77 (m, 2H), 1.71 (dd, J = 9.0, 5.0 Hz, 2H),1.17 (dd, J = 18.3, 6.0 Hz, 6H). LC-MS: [M + H]⁺ = 490.9, 491.9. 38

¹H NMR (400 MHz, CD₃OD) δ ppm 1.46-1.85 (4H, m), 2.80-3.00 (4H, m), 3.20(1H, t), 3.26 (3H, s), 3.46 (1H, d), 3.78 (3H, s), 5.53 (3H, s), 7.00(1H, t), 7.09 (1H, s), 7.33-7.46 (2H, m), 8.12 (2H, d), 8.34 (1H, s),LC-MS: [M + H]⁺ = 493.1. 39

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.24 (d, J = 2.7 Hz, 2H),7.57 (dd, J = 12.8, 2.2 Hz, 1H), 7.52-7.39 (m, 1H), 7.19 (s, 1H), 7.12(t, J = 8.6 Hz, 1H), 5.66 (s, 2H), 4.02 (q, J = 9.0 Hz, 2H), 3.59 (d, J= 9.0 Hz, 1H), 3.15 (d, J = 11.3 Hz, 1H), 3.10-2.86 (m, 3H), 1.97-1.85(m, 1H), 1.85- 1.50 (m, 3H). LC-MS: [M + H]⁺ = 560.8, 561.8. 40

¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.92 (4H, m), 2.94-3.14 (4H, m),3.84-4.04 (2H, dd), 5.66 (2H, s), 6.46 (1H, t), 7.07-7.11 (1H, m), 7.25(1H, s), 7.37-7.54 (3H, m), 8.23 (2H, d), 8.50 (1H, s). LC-MS: [M + H]+= 499.1. 41

¹H NMR (400 MHz, CD₃OD) δ ppm 8.40 (s, 1H), 8.12 (d, J = 2.4 Hz, 2H),7.65-7.60 (m, 1H), 7.43-7.41 (m, 1H), 7.20-7.13 (m, 1H), 6.54-6.17 (m,1H), 5.54 (s, 2H), 3.93 (d, J = 9.6 Hz, 1H), 3.75 (d, J = 10.0 Hz, 1H),3.02 (d, J = 11.6 Hz, 1H), 2.90-2.84 (m, 3H), 1.80-1.48 (m, 4H). LC- MS:[M + H]+ = 517.2. 42

¹H NMR (400 MHz, CD₃OD) δ 1.58-1.90 (4H, m), 2.98-3.14 (4H, m),3.84-4.05 (5H, m), 5.65 (2H, s), 6.46 (1H, t), 7.11 (1H, m), 7.19 (1H,s), 7.55 (2H, q), 8.23 (2H, d), 8.46 (1H, s). LC-MS: [M + H]+ = 529.1.43

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.24 (d, J = 1.4 Hz, 2H),7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.53 (ddt, J = 8.2, 4.0, 1.7 Hz,1H), 7.37-7.23 (m, 2H), 5.66 (s, 2H), 4.02 (q, J = 9.0 Hz, 2H), 3.86 (d,J = 9.0 Hz, 1H), 3.58 (d, J = 9.1 Hz, 1H), 3.16 (d, J = 11.2 Hz, 1H),3.11-2.83 (m, 3H), 1.92 (s, 1H), 1.86-1.66 (m, 2H), 1.66-1.51 (m, 1H).LC-MS: [M + H]+ = 548.8, 549.8. 44

¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.94 (4H, m), 2.95-3.15 (4H, m),3.85-4.05 (2H, dd), 5.66 (2H, s), 6.46 (1H, t), 7.10-7.15 (2H, m), 7.20(1H, s), 7.73-7.76 (2H, m), 8.23 (2H, d), 8.49 (1H, s). LC-MS: [M + H]+= 499.1 . 45

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.24 (s, 2H), 7.82-7.70 (m,2H), 7.23-7.09 (m, 3H), 5.67 (s, 2H), 4.03 (q, J = 9.0 Hz, 2H), 3.86 (d,J = 8.9 Hz, 1H), 3.59 (d, J = 9.0 Hz, 1H), 3.16 (d, J = 11.3 Hz, 1H),3.09-2.85 (m, 3H), 1.92 (s, 1H), 1.86-1.51 (m, 3H). LC-MS: [M + H]+ =530.8, 531.8. 46

¹H NMR (400 MHz, CD₃OD) δ ppm 8.34 (s ,1H), 8.12 (d, 2H), 7.46-7.33 (m,2H), 7.09 (s, 1H), 7.00 (t, 1H), 5.53 (s, 3H), 3.78 (s ,3H), 3.46 (d,1H), 3.26 (s, 3H), 3.20 (t ,1H), 3.00-2.80 (m, 4H), 1.85-1.46 (m, 4H).LC-MS: [M + H]+ = 493.1.

Example 47:(S)-9-((5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine

To a solution of methyl 2-(3,4-difluorophenyl)-5-fluoroisonicotinate(Intermediate A) (1.35 g, 5.05 mmol) and tert-butyl(3-(2,2-difluoroethyl)piperidin-3-yl)carbamate (Intermediate 47-6) (1.3g, 5.05 mmol) in DMSO (30 mL) was added DIPEA (20 mL) at rt, thereaction mixture was stirred at 120° C. for 8 hr under N₂ atmosphere.The reaction mixture was diluted with water, extracted with EtOAc (20mL*3), the combined organic phase was washed with water (20 mL), brine(20 mL), dried over anhydrous sodium sulfate, concentrated to give acrude product. The crude product was purified by flash chromatography(elution gradient: 0% to 30% EtOAc in PE in 30 mins) to afford methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(47-7). LC-MS: [M+H]⁺=512.0.

To a solution of methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(47-7) (1.2 g, 2.346 mmol) in THF (30 mL) and Methanol (30 mL), wasadded lithium chloride (1.97 g, 46.9 mmol) and sodium tetrahydroborate(1.78 g, 46.9 mmol) at rt, the reaction mixture was stirred at rt for 5h under N₂ atmosphere. The reaction mixture was diluted with water (20mL), extracted with EtOAc (20 mL*3), the combined organic phase waswashed with water (20 mL), brine (20 mL), dried over anhydrous sodiumsulfate, concentrated to give a residue. The residue was purified byflash chromatography (elution gradient: 10% to 50% EtOAc in hexane in 30mins) to afford tert-butyl(3-(2,2-difluoroethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(47-8). LC-MS: [M+H]⁺=484.2.

To a solution of tert-butyl(3-(2,2-difluoroethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(47-8) (865 mg, 1.789 mmol), Intermediate B (600 mg, 1.789 mmol) andtriphenylphosphine (939 mg, 3.58 mmol) and in THF (20 mL), was addedDEAD (0.567 mL, 3.58 mmol) dropwise at 0° C., the reaction mixture wasstirred at 0° C. for 0.5 hr under N₂ atmosphere. The reaction mixturewas diluted with water (20 mL), extracted with EtOAc (20 mL*3), thecombined organic phase was washed with water (10 mL), brine (20 mL),dried over sodium sulfate, concentrated to give a crude product. Thecrude product was purified by flash chromatography (elution gradient: 0%to 10% MeOH in DCM in 30 mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(47-9). LC-MS: [M+H]⁺=801.1.

To a solution of tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(47-9) (700 mg, 0.875 mmol) in DCM (18 mL) was added TFA (6 mL), thereaction mixture was stirred at RT for 2 hr under N₂ atmosphere. Thereaction mixture was concentrated in vacuo to give the crude product.The crude product was purifed by Pre-HPLC (Basic condition, NH₃H₂O%=0.05%, MECN/H₂O=0-95% in 12 mins) to afford the pure racemic product.The racemic product was isolated by SFC to afford(S)-9-((5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine(Example 47). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.23 (d, J=3.9 Hz,2H), 7.75 (ddd, J=12.2, 7.8, 2.2 Hz, 1H), 7.53 (s, 1H), 7.34-7.22 (m,2H), 6.38-6.02 (m, 1H), 5.73-5.52 (m, 2H), 3.00 (d, J=9.4 Hz, 3H), 2.92(d, J=10.5 Hz, 1H), 2.11 (q, J=18.5, 18.0 Hz, 2H), 1.92 (s, 1H), 1.73(d, J=28.9 Hz, 3H). LC-MS: [M+H]⁺=501.3.

Example 48-77 can be prepared following procedures analogous to thosedescribed in Example 47, from corresponding intermediates.

Example # Structure ¹H NMR & MS 48

¹H NMR (400 MHz, CD₃OD) δ: 8.47-8.58 (m, 1H), 8.26 (s, 1H), 7.76 (d, J =3.5 Hz, 1H), 7.68 (d, J = 6.0 Hz, 2H), 7.48 (d, J = 3.5 Hz, 1H), 7.38-7.46 (m, 1H), 7.24 (dt, J = 10.3, 8.5 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H),5.64-5.77 (m, 2H), 3.25-3.42 (m, 4H), 3.13 (br d, J = 11.0 Hz, 1H),2.93-3.05 (m, 3H), 1.86-1.99 (m, 2H), 1.65-1.77 (m, 1H), 1.52-1.64 (m,1H). LC-MS: [M + H]+ = 533.1. 49

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.25 (s, 1H), 7.69 (q, J =4.1, 2.3 Hz, 3H), 7.50 (d, J = 2.1 Hz, 1H), 7.21-6.94 (m, 3H), 6.69 (d,J = 6.1 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H), 5.70 (s, 2H), 3.85 (s, 3H),3.07 (dd, J = 11.7, 6.3 Hz, 2H), 2.91 (d, J = 21.9 Hz, 4H), 1.92 (dtq, J= 29.4, 10.3, 5.0, 4.6 Hz, 2H), 1.63 (dtd, J = 29.5, 13.2, 4.8 Hz, 2H).LC-MS: [M + H]+ = 512.1, 513.0. 50

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (d, J = 4.4 Hz, 1H), 8.44 (s, 1H),8.23 (s, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.49(dd, J = 12.4 Hz, 2.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.29 (t, J =8.0 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.68 (d, J = 6.0Hz, 1H), 5.68 (s, 2H), 3.86 (s, 3H), 3.13-3.00 (m, 4H), 2.97- 2.85 (m,2H), 2.00-1.80 (m, 2H), 1.72-1.52 (m, 2H). LC-MS: [M + H]+ = 539.3. 51

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55-8.46 (m, 2H), 8.24 (s, 1H), 7.76(t, J = 7.6 Hz, 1H), 7.71-7.63 (m, 2H), 7.47-7.40 (m, 1H), 7.36 (d, J =7.6 Hz, 1H), 7.31-7.21 (m, 2H), 7.07 (s, 1H), 6.67 (d, J = 6.0 Hz, 1H),5.69 (s, 2H), 3.16-3.02 (m, 4H), 2.95-2.88 (m, 2H), 2.02-1.81 (m, 2H),1.71-1.54 (m, 2H). LC-MS: [M + H]+ = 527.2 [M + H]+. 52

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.48 (s, 1H), 8.29 (s, 1H), 8.11 (s,1H), 8.01 (s, 1H), 7.97- 7.80 (m, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.56-7.43 (m, 1H), 7.31 (d, J = 14.8 Hz, 3H), 7.13 (s, 1H), 5.71-5.44 (m,2H), 3.13-2.82 (m, 6H), 2.06- 1.63 (m, 4H), 1.65-1.40 (m, 2H) LC-MS:[M + H]⁺ = 518.2, 519.2. 53

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (s, 1H), 8.29 (s, 1H), 8.12 (s,1H), 7.90-7.84 (m, 1H), 7.71 (d, J = 3 2 Hz, 1H), 7.63-7.55 (m, 2H),7.51-7.44 (m, 1H), 7.30 (d, J = 10.8 Hz, 2H), 5.61-5.59 (m, 2H), 3.31(m, 2H), 3.18 (d, J = 14.4 Hz, 1H), 2.95-2.82 (m, 4H), 1.85-1.70 (m,2H), 1.58-1.48 (m, 1H), 1.46-1.39 (m, 1H). LC-MS: [M + H]⁺ = 534.1. 54

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (d, J = 3.6 Hz, 1H), 8.43 (s, 1H),8.29 (s, 1H), 8.09 (s, 1H), 7.88-7.81 (m, 1H), 7.66 (dt, J = 2.0 Hz, 7.6Hz, 1H), 7.61-7.55 (m, 1H), 7.50-7.41 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H),7.30-7.22 (m, 2H), 7.21- 7.16 (m, 2H), 5.55 (q, J = 16.4 Hz, 2H),3.01-2.75 (m, 6H), 2.05 (brs, 2H), 1.85-1.70 (m, 2H), 1.55-1.43 (m, 1H),1.42-1.30 (m, 1H). LC-MS: [M + H]⁺ = 528.2. 55

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (s, 1H), 8.23 (s, 1H), 7.81-7.74(m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 6.0 Hz, 1H), 7.54 (d, J= 7 6 Hz, 1H), 7.25-7.16 (m, 2H), 7.13-7.05 (m, 2H), 6.54 (d, J = 6.0Hz, 1H), 6.19 (s, 2H), 5.54 (s, 2H), 3.53-3.45 (m, 1H), 3 18-3.09 (m,1H), 3.04-2.99 (m, 1H), 2.98-2 89 (m, 1H), 2 48 (s, 3H), 2.34-2.16 (m,3H), 2.15-2.04 (m, 1H), 1.81-1.72 (m, 1H), 1.70-1.63 (m, 1H). LC-MS:[M + H]⁺ = 509.3. 56

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.23 (d, J = 3.8 Hz, 2H),7.74 (ddd, J = 12.1, 7.7, 2.2 Hz, 1H), 7.51 (dd, J = 14.3, 4.2 Hz, 2H),7.29 (d, J = 10.3 Hz, 2H), 6.17 (d, J = 2.2 Hz, 1H), 5.74-5.56 (m, 2H),3.86 (s, 3H), 3.03 (d, J = 11.2 Hz, 2H), 2.88 (d, J = 26.8 Hz, 4H),2.00-1.74 (m, 2H), 1.62 (q, J = 5.8, 5.4 Hz, 2H). LC-MS: [M + H]⁺ =531.0, 532.0. 57

¹H NMR (400 MHz, CD₃OD) δ ppm 8.39 (s, 1H), 8.21 (s, 1H), 7.72 (d, J =3.2 Hz, 1H), 7.66 (d, J = 6 Hz, 1H), 7.50-7.49 (m, 2H), 7.31 (d, J = 8.8Hz, 1H), 6.96 (t, J = 7.6 Hz, 2H), 6.67 (d, J = 6.0 Hz, 1H), 5.72-5.59(m, 2H), 3.79 (s, 3H), 3.40- 3.20 (m, 2H), 3.05 (d, J = 11.2 Hz, 1H),2.95- 2.85 (m, 3H), 1.95-1.76 (m, 2H), 1.70-1.60 (m, 1H), 1.55-1.45 (m,1H). LC-MS: [M + H]+ = 545.2 58

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1 H), 8.32 (s, 1 H), 8.23 (s, 1H), 7.52-7.47 (m, 2 H), 7.42-7.36 (m, 1H), 7.20 (s, 1 H), 7.11-7.07 (m,1H), 5.72-5.63 (m, 2 H), 3.15-2.94 (m, 4 H), 2.56-2.47 (m, 2 H),1.96-1.64 (m, 4 H). LC-MS: [M + H]⁺ = 477.1. 60

¹H NMR (400 MHz, CD₃OD) δ: 8.51 (s, 1H), 8.24 (d, J = 4.0 Hz, 2H), 7.76(ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.60-7.47 (m, 1H), 7.39-7.16 (m, 2H),5.89-5.55 (m, 2H), 3.60 (td, J = 6.4, 2.3 Hz, 2H), 3.35 (s, 3H), 2.97(dp, J = 24.6, 11.2 Hz, 4H), 2.04-1.71 (m, 4H), 1.65 (d, J = 7.3 Hz,2H). LC-MS: [M + H]+ = 495.2 61

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J = 2.5 Hz, 1H), 8.32-8.16 (m, 2H),7.58 (dt, J = 12.7, 1.8 Hz, 1H), 7.53-7.42 (m, 1H), 7.25 (s, 1H),7.20-6.97 (m, 1H), 6.41-6.00 (m, 1H), 5.83- 5.51 (m, 2H), 3.90 (d, J =1.4 Hz, 3H), 3.07-2.80 (m, 4H), 2.33-1.99 (m, 2H), 1.93 (s, 1H),1.82-1.55 (m, 3H). LC-MS: [M + H]⁺ = 512.8, 513.8. 62

¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (s, 1H), 8.39 (s, 1H), 7.92 (s, 1H),7.66-7.77 (m, 2H), 7.48 (br d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 5.76 (brs, 2H), 5.47-5.58 (m, 2H), 2.92-3.12 (m, 4H), 2.42-2.49 (m, 1H), 2.15(d, J = 4.3 Hz, 1H), 1.59- 1.79 (m, 4H). LC-MS: [M + H]⁺ = 493.8. 63

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H),7.74-7.64 (m, 2H), 7.45 (ddt, J = 8.3, 4.0, 1.7 Hz, 1H), 7.27 (dt, J =10.6, 8.4 Hz, 1H), 7.15 (s, 1H), 7.07 (s, 1H), 6.70 (d, J = 6.0 Hz, 1H),5.80-5.60 (m, 2H), 3.24- 3.04 (m, 4H), 3.04-2.99 (m, 2H), 2.01-1.88 (m,2H), 1.68 (dp, J = 28.2, 7.3, 6.5 Hz, 2H). LC- MS: [M + H]+ = 517.2,518.2. 64

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55-8.61 (m, 1H), 8.52 (s, 1H), 8.38 (s,1H), 7.74-7.80 (m, 2H), 7.66-7.73 (m, 2H), 7.39 (s, 1H), 6.21-6.53 (m,1H), 5.85 (br d, J = 12.5 Hz, 2H), 3.73 (t, J = 6.4 Hz, 2H), 3.42 (s,2H), 3.01 (t, J = 6.4 Hz, 2H), 2.42-2.62 (m, 2H), 1.94-2.18 (m, 4H),1.35- 1.41 (m, 2H). LC-MS: [M + H]+ = 613.9. 65

¹H NMR (400 MHz, CD₃OD) δ ppm 8.62-8.40 (m, 2H), 8.25 (s, 2H), 7.77 (q,J = 7.7 Hz, 2H), 7.56 (q, J = 3.4 Hz, 1H), 7.44-7.14 (m, 4H), 5.82-5.55(m, 2H), 3.18-3.08 (m, 2H), 3.00 (dd, J = 11.9, 6.2 Hz, 2H), 2.87 (t, J= 10.4 Hz, 1H), 1.88 (t, J = 9.8 Hz, 1H), 1.80-1.65 (m, 1H), 1.55 (td, J= 12.3, 10.9, 4.5 Hz, 1H), 1.34 (t, J = 11.2 Hz, 4H). LC-MS: [M + H]⁺ =542.0, 543.0. 66

¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H),7.54-7.49 (m, 2H), 7.43- 7.37 (m, 1H), 7.24 (s, 1H), 7.11-7.07 (m, 1H),5.72-5.63 (m, 2H), 3.10-2.94 (m, 4H), 2.72 (s, 3H), 2.49 (s, 2H),1.90-1.66 (m, 4H). LC-MS: [M + H]+ = 490.2 67

¹H NMR (400 MHz, CD₃OD) δ: 8.49 (s, 1H), 8.32 (s, 1H), 7.73-7.55 (m,2H), 7.38 (d, J = 8.7 Hz, 1H), 7.26 (dt, J = 10.4, 8 4 Hz, 1H), 6.79 (s,1H), 5.95 (s, 2H), 3.19-2.99 (m, 4H), 2.74 (s, 3H), 2.55 (q, J = 14.9Hz, 2H), 1.93 (d, J = 39.7 Hz, 2H), 1.70 (s, 2H). LC-MS: [M + H]+ =540.8 68

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (d, J = 6.1 Hz, 1H), 8.32 (d, J = 6.1Hz, 1H), 7.63 (h, J = 6.6 Hz, 2H), 7.37 (s, 1H), 7.26 (q, J = 8.4 Hz,1H), 6.79 (d, J = 6.2 Hz, 1H), 5.90 (d, J = 6.5 Hz, 2H), 3.07 (dd, J =14.0, 7.4 Hz, 7H), 2.96-2.75 (m, 4H), 2.61 (dd, J = 16.5,6.4 Hz, 1H),1.94 (d, J = 25.0 Hz, 2H), 1.74 (s, 2H). LC-MS: [M + H]+ = 554.8, 556.7.69

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H),7.86 (q, J = 8.0 Hz, 1H), 7.76-7.65 (m, 1H), 7.54-7.46 (m, 1H), 7.30-7.20 (m, 3H), 6.90 (dd, J = 2.4, 8.0 Hz, 1H), 5.76- 5.58 (m, 2H),3.09-2.86 (m, 6H), 1.96-1.76 (m, 2H), 1.72-1.51 (m, 2H). LC-MS: [M + H]+= 546.4. 70

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.14 (s, 1H), 8.12 (s, 1H),7.43-7.38 (m, 2H), 7.31- 7.26 (m, 1H), 7.14 (s, 1H), 7.00-6.96 (m, 1H),5.54-5.51 (m, 2H), 3.09-2.92 (m, 6H), 2.88-2.78 (m, 4H), 2.67-2.60 (m,1H), 2.52-2.48 (m, 1H), 1.88-1.57 (m, 4H). LC-MS: [M + H]+ = 504.2. 71

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.24 (t, J = 3.0 Hz, 2H),7.78 (dt, J = 8.4, 4.3 Hz, 2H), 7.25 (s, 1H), 7.15 (t, J = 8.5 Hz, 2H),6.22 (tt, J = 56.3, 4.7 Hz, 1H), 5.93-5.53 (m, 2H), 3.13-2.79 (m, 4H),2.34-1.86 (m, 3H), 1.86- 1.54 (m, 3H). LC-MS: [M + H]+ = 482.9, 483.9.72

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.28 (s, 1H), 7.76-7.63 (m,2H), 7.44 (ddt, J = 8.3, 3.9, 1.6 Hz, 1H), 7.27 (dt, J = 10.5, 8.5 Hz,1H), 7.04 (s, 1H), 6.66 (d, J = 6.0 Hz, 1H), 5.71 (s, 2H), 3.21-2.91 (m,4H), 2.74 (s, 3H), 2.55 (s, 2H), 1.97 (d, J = 11.2 Hz, 1H), 1.88 (d, J =5.2 Hz, 1H), 1.72 (d, J = 4.7 Hz, 2H). LC-MS: [M + H]+ = 506.9, 507.9.73

¹H NMR (400 MHz, CD₃OD) δ ppm 8.37 (s, 1 H), 8.13 (s, 1 H), 8.10 (s, 1H), 7.44-7.39 (m, 2 H), 7.31-7.26 (m, 1H), 7.18 (s, 1 H), 7.00-6.96 (m,1H), 5.60-5.49 (m, 2 H), 3.57 (s, 3 H), 2.98-2.86 (m, 4 H), 2.56-2.45(m, 2 H), 1.82-1.56 (m, 4 H). LC-MS: [M + H]+ = 491.2. 74

¹H NMR (400 MHz, CD₃OD) δ ppm 8.68-8.56 (m, 2H), 8.56-8.43 (m, 2H), 8.24(d, J = 3.5 Hz, 2H), 7.76 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.54 (ddt, J= 8.2, 3.8, 1.7 Hz, 1H), 7.38-7.17 (m, 2H), 5.82-5.51 (m, 2H), 3.21-3.05(m, 3H), 2.97 (t, J = 8.5 Hz, 3H), 1.88 (d, J = 9.1 Hz, 2H), 1.70 (dt, J= 13.8, 6.5 Hz, 1H), 1.61 (q, J = 7.6, 6.4 Hz, 1H). LC-MS: [M + H]+ =529.2, 530.2. 75

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H),7.79 (br d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.39 (br d, J = 8.0 Hz, 2H),6.20- 6.53 (m, 1H), 5.65 (br d, J = 3.0 Hz, 2H), 4.46 (s, 2H), 4.11 (s,2H), 3.06 (br s, 2H), 2.98 (br s, 2H), 2.40-2.54 (m, 2H), 1.87-2.03 (m,4H). LC-MS: [M + H]+ = 570.0. 76

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55-8.59 (m, 1H), 8.47-8.51 (m, 1H), 8.36(s, 1H), 7.73- 7.81 (m, 4H), 7.37 (s, 1H), 6.42-6.48 (m, 1H), 6.41 (d, J= 2.5 Hz, 1H), 6.21-6.39 (m, 1H), 5.77- 5.84 (m, 3H), 3.40 (br d, J =4.3 Hz, 2H), 3.12- 3.22 (m, 1H), 3.01-3.09 (m, 1H), 2.43-2.60 (m, 2H),2.04 (br d, J = 11.0 Hz, 4H) LC-MS: [M + H]+ = 534.0. 77

¹H NMR (CD₃OD) δ: 8.55 (s, 1H), 8.28 (d, J = 20.9 Hz, 2H). 7.80 (t, J =10.0 Hz, 1H), 7.59 (s, 1H), 7.45-7.23 (m, 2H), 5.66 (s, 2H), 3.22 (t, J= 9.4 Hz, 2H), 3.08-2.86 (m, 4H), 2.23 (s, 2H), 1.90 (d, J = 8.8 Hz, 4H)LC-MS: [M + H]+ = 475.8

Example 78:(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)-N-methylpiperidine-3-carboxamide

To a solution of methyl tert-butyl3-(methylcarbamoyl)piperidin-3-ylcarbamate (Intermediate 78-5) (200 mg,0.777 mmol), methyl 5-fluoro-2-(3-fluorophenyl)isonicotinate(Intermediate C) (161 mg, 0.648 mmol) in DMSO (4 mL) was added DIPEA (4mL) at RT, the reaction mixture was stirred at 120° C. overnight. Thereaction mixture was diluted with water, extracted with EtOAc, thecombined organic phase was washed with water (20 mL), brine (20 mL),dried over anhydrous sodium sulfate, concentrated to give a residue. Theresidue was purified by flash chromatography (elution gradient: 0% to30% EtOAc in PE in 30 mins) to afford methyl5-(3-(tert-butoxycarbonylamino)-3-(methylcarbamoyl)piperidin-1-yl)-2-(3-fluorophenyl)isonicotinate (78-6). LC-MS: [M+H]⁺=487.3.

To a mixture of methyl5-(3-(tert-butoxycarbonylamino)-3-(methylcarbamoyl)piperidin-1-yl)-2-(3-fluorophenyl)isonicotinate (78-6) (150 mg, 0.308 mmol), LiCl (130 mg, 3.08 mmol), THF(5 mL) and MeOH (5 mL) was added NaBH₄ (232 mg, 6.16 mmol) portionwise.After addition, the mixture was stirred at RT for 3 h. Then water (10mL) was added to quench the reaction, extracted with EtOAc, the combinedorganic phase was washed with water (20 mL), brine, dried over anhydroussodium sulfate, concentrated to give a residue. The residue was purifiedby flash chromatography (elution gradient: 10% to 50% EtOAc in PE in 30mins) to give tert-butyl1-(6-(3-fluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(methylcarbamoyl)piperidin-3-ylcarbamate(78-7). LC-MS: [M+H]⁺=459.2.

To a solution of tert-butyl1-(6-(3-fluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(methylcarbamoyl)piperidin-3-ylcarbamate(78-7) (129 mg, 0.282 mmol), Intermediate B (142 mg, 0.423 mmol), n-Bu3P(171 mg, 0.845 mmol) in THF (5 mL) was added DIAD (171 mg, 0.845 mmol)dropwise at RT under N₂ atmosphere, after addition, the mixture wasstirred at RT for 1 h under N₂, quenched with water and extracted withEtOAc. The combined organic phase was worked up under aqueous conditionsand concentrated to give a residue. The residue was purified by flashchromatography (elution gradient: 10% to 70% EtOAc in PE in 30 mins) toafford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)piperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(78-8). LC-MS: [M+H]⁺=776.3

To a solution of tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)piperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(78-8) (100 mg, 0.232 mmol) in DCM (9 mL), was added TFA (3 mL) at RT.The reaction mixture was stirred at RT for 1 h. The mixture wasconcentrated in vacuo to give a residue. The residue was purified byPre-HPLC (Basic condition, NH₃H₂O %=0.05%, MEOH/H₂O=0-95% in 12 mins) toafford 40 mg of pure racemic product. The racemic product was isolatedby SFC to give(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)-N-methylpiperidine-3-carboxamide(Example 78). ¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.17 (s, 1H), 8.11(s, 1H), 7.44-7.39 (m, 2H), 7.32-7.27 (m, 1H), 7.18 (s, 1H), 7.01-6.97(m, 1H), 5.62-5.51 (m, 2H), 3.32-3.29 (m, 1H), 3.02-2.99 (m, 1H),2.91-2.78 (m, 2H), 2.69 (s, 3H), 2.09-2.01 (m, 1H), 1.97-1.87 (m, 1H),1.70-1.67 (m, 1H), 1.55-1.51 (m, 1H). LC-MS: [M+H]⁺=476.2

Example 79-88 can be prepared following procedures analogous to thosedescribed in Example 78.

Example # Structure ¹H NMR & MS 79

¹H NMR (400 MHz, CDCl₃ ) δ ppm 8.54 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H),7.59-7.47 (m, 2H), 7.40-7.30 (m, 2H), 7.04 (td, J = 8.2, 2.1 Hz, 1H),5.67 (s, 2H), 5.60-5.46 (m, 2H), 3.79 (s, 3H), 3.48 (d, J = 11.4 Hz,1H), 3.01 (dd, J = 13.7, 8.4 Hz, 3H), 2.21 (d, J = 5.4 Hz, 1H),2.04-1.86 (m, 2H), 1.67-1.59 (m, 1H). LC-MS: [M + H]⁺ = 477.1. 80

¹H NMR (400 MHz, CD₃OD) δ 8.37(1H, s), 8.17 (1H, s), 8.12 (1H, s), 7.45(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.12(1H, s),6.99 (1H, t, J = 8.8 Hz), 5.48-5.62 (2H, m), 3.78 (3H, s), 3.34-3.37(1H, m), 2.98-3.20 (8H, m), 2.68-2.74 (1H, m), 1.86-1.96 (2H, m),1.67-1.82 (2H, m). LC-MS: [M + H]⁺ = 520.2. 81

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.13 (s, 2H), 7.47-7.43 (m, 1H),7.35-7.33 (m, 1H), 7.13 (s, 1H), 7.01-6.97 (m, 1H), 5.56-5.47 (m, 2H),4.98-4.92 (m, 1H), 3.77 (s, 3H), 3.38 (d, J = 11.2 Hz, 1H), 2.89-2.86(m, 3H), 2.08-2.04 (m, 1H), 1.83-1.77 (m, 2H), 1.59-1.57 (m, 1H),1.19-1.16 (m, 6H). LC-MS: [M + H]⁺ = 535.2. 82

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.23 (d, J = 15.0 Hz, 2H),7.74 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.52 (ddt, J = 7.5, 3.5, 1.7 Hz,1H), 7.39-7.21 (m, 2H), 6.05-5.41 (m, 2H), 3.90 (tdd, J = 15.3, 7.9, 4.1Hz, 3H), 3.62-3.33 (m, 3H), 3.15-3.04 (m, 1H), 3.00-2.79 (m, 2H),2.27-1.91 (m, 2H), 1.90-1.73 (m, 3H), 1.57 (dddd, J = 17.4, 15.8, 8.9,5.2 Hz, 3H). LC-MS: [M + H]⁺ = 564.2, 565.2. 83

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.24 (d, J = 5.3 Hz, 2H),7.56 (dd, J = 12.7, 2.1 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.21 (s, 1H),7.11 (t, J = 8.7 Hz, 1H), 5.73-5.52 (m, 2H), 3.89 (s, 3H), 3.46 (d, J =11.3 Hz, 1H), 3.08- 2.88 (m, 3H), 2.14 (s, 1H), 1.91 (d, J = 17.6 Hz,2H), 1.67 (s, 1H), 1.51 (s, 9H). LC-MS: [M + H]⁺ = 549.1. 84

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.39-8.14 (m, 2H), 7.64 (d,J = 86.3 Hz, 2H), 7.30 (s, 2H), 5.65 (q, J = 15.9 Hz, 2H), 3.84 (d, J =55.4 Hz, 2H), 3.50 (d, J = 12.3 Hz, 3H), 3.11 (d, J = 11.1 Hz, 2H), 2.86(s, 1H), 1.89 (d, J = 47.7 Hz, 8H). LC-MS: [M + H]⁺ = 534.3, 535.3. 85

¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H),7.81-7.63 (m, 1H), 7.55- 7.44 (m, 1H), 7.36-7.19 (m, 2H), 5.77-5.57 (m,2H), 4.44-4.32 (m, 1H), 3.97-3.74 (m, 3H), 3.68- 3.62 (m, 1H), 3.39 (d,J = 11.2 Hz, 1H), 3.13-2.81 (m, 3H), 2.31-1.54 (m, 6H). LC-MS: [M + H]⁺= 572.1 86

¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H),7.78-7.69 (m, 1H), 7.56-7.49 (m, 1H), 7.34-7.22 (m, 2H), 5.75-5.56 (m,2H), 3.81 (br s, 4H), 3.46 (d, J = 12.0 Hz, 1H), 3.20-3.06 (m, 2H),2.92-2.74 (m, 1H), 2.10- 1.54(m, 10H). LC-MS: [M + H]⁺ = 548.1. 87

¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.21(s, 1H), 7.80-7.67 (m, 1H), 7.58-7.45 (m, 1H), 7.34-7.21 (m, 2H),5.77-5.55 (m, 2H), 5.47-4.90(m, 1H), 4.83-4.22 (m, 1H), 3.53-3.35 (m,1H), 3.19-2.68 (m, 4H), 2.10-1.17 (m, 13H). LC-MS: [M + H]⁺ = 562.2 88

¹H NMR (400 MHz, CD₃OD) δ ppm 8.79-8.49 (m, 1H), 8.27 (dd, J = 31.2, 5.8Hz, 2H), 7.86- 7.50 (m, 2H), 7.34 (s, 2H), 5.65 (q, J = 16.2 Hz, 2H),4.23 (s, 1H), 4.03 (s, 1H), 3.90-3.73 (m, 1H), 3.57(d, J = 11.7 Hz, 1H),3.23-3.04 (m, 2H), 2.92 (d, J = 10.1 Hz, 1H), 2.11-1.80 (m, 7H), 1.55(s, 1H), 1.21 (d, J = 6.4 Hz, 3H). LC- MS: [M + H]⁺ = 548.3, 549.3.

Example 89:1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,3-dimethylbutan-1-one

To a solution of methyl(3-(2,3-dimethylbutanoyl)piperidin-3-yl)carbamate (Intermediate 89-6)(367 mg, 1.4 mmol, 1.0 eq.) and methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate (Intermediate A) (383 mg,1.4 mmol, 1.0 eq.) in DMSO (10 mL) was added DIPEA (724 mg, 5.6 mmol,4.0 eq.). The mixture was stirred at 120° C. for 5 hours under N₂atmosphere. The mixture was diluted with H₂O (20 mL), extracted withEtOAc (20 mL*2). The combined organic layers were washed with brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (30% EtOAcin PE) to give methyl2-(3,4-difluorophenyl)-5-(3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)isonicotinate (89-7). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.52(s, 0.5H), 8.50 (s, 0.5H), 8.02 (s, 0.5H), 7.98 (s, 0.5H), 7.94-7.86 (m,1H), 7.80-7.73 (m, 1H), 7.39-7.30 (m, 1H), 4.00 (s, 1.5H), 3.99 (s,1.5H), 3.75 (d, J=12.4 Hz, 0.5H), 3.67 (d, J=12.0 Hz, 0.5H), 3.59 (s,1.5H), 3.54 (s, 1.5H), 3.42-3.34 (m, 1H), 3.23 (d, J=12.4 Hz, 0.5H),3.13-3.00 (m, 1.5H), 2.97-2.88 (m, 1H), 2.30-2.20 (m, 1H), 2.01-1.82 (m,3H), 1.78-1.66 (m, 1H), 0.99-0.94 (m, 3H), 0.90-0.84 (m, 6H). LC-MS:[M+H]⁺=504.2.

To a mixture of methyl2-(3,4-difluorophenyl)-5-(3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)isonicotinate (89-7) (416 mg, 0.82 mmol, 1.0 eq.) inCH₃OH (10 mL) was added NaBH₄ (312 mg, 8.2 mmol, 10 eq.) at RT. Themixture was stirred at RT for 20 minutes. Another NaBH₄ (312 mg, 8.2mmol, 10 eq.) was added and the mixture was stirred at RT for another 20minutes. The mixture was diluted with H₂O (20 mL), extracted with EtOAc(20 mL*2). The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (30% EtOAc inhexane) to give methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(1-hydroxy-2,3-dimethylbutyl)piperidin-3-yl)carbamate(89-8). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.34 (s, 0.4H), 8.33 (s, 0.6H),7.91 (s, 0.4H), 7.90 (s, 0.6H), 7.88-7.81 (m, 1H), 7.76-7.70 (m, 1H),7.39-7.32 (m, 1H), 4.84-4.69 (m, 1H), 3.90-3.64 (m, 1H), 3.63-3.55 (m,3H), 3.49-3.43 (m, 0.3H), 3.28-3.23 (m, 0.6H), 3.18-3.02 (m, 2H),2.86-2.76 (m, 1H), 2.31-2.15 (m, 1H), 2.00-1.86 (m, 1H), 1.82-1.54 (m,3H), 1.21-1.20 (m, 1H), 0.95-0.78 (m, 9H). LC-MS: [M+H]⁺=478.2.

To a solution of methyl(1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)-3-(1-hydroxy-2,3-dimethylbutyl)piperidin-3-yl)carbamate(intermediate 89-8) (273 mg, 0.57 mmol, 1.0 eq.), Intermediate B (192 mg0.57 mmol 1.0 eq.) and Bu₃P (578 mg, 2.86 mmol, 5.0 eq.) in THF (15 mL)was added DIEA (578 mg, 2.86 mmol, 5.0 eq.) dropwise at 0° C. under N₂.Then the reaction mixture was stirred at RT for 1 hour under N₂. Themixture was diluted with H₂O (20 mL), extracted with EtOAc (20 mL*2).The combined organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (50% EtOAc in PE) to givetert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-(1-hydroxy-2,3-dimethylbutyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(89-9). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.91-8.81 (m, 1H), 8.80-8.70 (m,1H), 8.56-8.50 (m, 1H), 7.76-7.67 (m, 1H), 7.59-7.51 (m, 1H), 7.36-7.23(m, 2H), 5.92-5.64 (m, 2H), 4.04-3.65 (m, 2H), 3.60-3.48 (m, 3H),3.30-2.75 (m, 3H), 2.33-2.13 (m, 2H), 1.88-1.70 (m, 4H), 1.36 (s, 18H),0.98-0.93 (m, 9H). LC-MS: [M+H]⁺=795.3.

A mixture of tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-(1-hydroxy-2,3-dimethylbutyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(89-9) (279 mg, 0.37 mmol, 1.0 eq.) and DMP (237 mg 0.56 mmol, 1.5eq.)in DCM (10 ml) was stirred at RT for 4 hours. The mixture was quenchedwith sat. aq. NaHCO₃ (30 mL), extracted with DCM (30 mL*2). The combinedorganic layers were washed with sat. aq. NaHCO₃ (20 mL*2), brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by silica gel columnchromatography (50% EtOAc in PE) to give tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(89-10). LC-MS: [M+H]⁺=793.5.

A mixture of tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-(2,3-dimethylbutanoyl)-3-((methoxycarbonyl)amino)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(89-10) (280 mg, crude, 0.34 mmol, 1 eq.) and 10 ml of 35% HBr in aceticacid was stirred at RT for 20 hours. LC-MS showed most of startingmaterial was consumed. The reaction mixture was concentrated in vacuoand diluted with H₂O (30 mL), washed with EtOAc (30 mL*3) to removeimpurities. The aqueous layer was basified by NH₃.H₂O to pH=11,extracted with EtOAc (30 mL*2), The organic layers were dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by prep-HPLC to give 1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl) pyridin-3-yl)piperidin-3-yl)-2,3-dimethylbutan-1-one (Example 89). ¹H NMR (400 MHz,CD₃OD) δ 8.52 (d, J=4.0 Hz, 1H), 8.32-8.17 (i, 2H), 7.83-7.65 (n, 1 OH),7.60-7.48 (m, 1H), 7.37-7.15 (i, 2H), 5.67 (d, J=3.6 Hz, 2H), 3.41 (t,J=12.0 Hz, 1H), 3.14-2.87 (m, 4H), 2.08-1.61 (m, 5H), 1.06 (t, J=8.0 Hz,3H), 0.95 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H). LC-MS:[M+H]⁺=535.3.

Example 90-112 can be prepared following procedures analogous to thosedescribed in Example 89.

Example # Structure ¹H NMR & MS 90

¹H NMR (400 MHz, CD₃OD) δ 8.48 (dd, J = 13.4, 7.8 Hz, 1H), 8.36-8.15 (m,2H), 7.66- 7.36 (m, 2H), 7.27 (dd, J = 13.5, 7.9 Hz, 1H), 7.14 (dd, J =14.3, 7.0 Hz, 1H), 5.77-5.51 (m, 2H), 4.02-3.82 (m, 3H), 3.70 (d, J =14.0 Hz, 1H), 3.21-3.00 (m, 2H), 3.00-2.75 (m, 2H), 1.96 (s, 1H), 1.73(d, J = 37.1 Hz, 3H), 1.25 (p, J = 7.4, 6.2 Hz, 3H). LC-MS: [M + H]⁺ =493.0 91

¹H NMR (400 MHz, CD₃OD) δ 8.57-8.51 (m, 1H), 8.45 (s, 1H), 8.25 (s, 1H),8.21 (s, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.73 (ddd, J = 12.0, 7.7,2.2 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz,1H), 7.51 (dddd, J = 8.5, 3.9,2.2, 1.3 Hz, 1H), 7.37 (ddd, J = 7.7, 4.9, 1.1 Hz, 1H), 7.32-7.22 (m,2H), 5.77-5.56 (m, 3H), 3.18 (d, J = 11.4 Hz, 1H), 2.96 (tq, J = 18.3,9.1, 8.2 Hz, 3H),2.02-1.82 (m 3H), 1.71 (dd, J = 11.0, 6.0 Hz, 1H).LC-MS: [M + H]⁺ = 546.3 92

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.27 (d, J = 13.6 Hz, 2H), 7.57(dd, J = 12.6, 2.3 Hz, 1H), 7.53-7.42 (m, 1H), 7.21 (s, 1H), 7.13(t, J =8.7 Hz, 1H), 5.69 (d, J = 2.7 Hz, 2H), 3.90 (s, 4H), 3.06 (d, J = 16.7Hz, 3H), 2.92 (d, J = 10.5 Hz, 1H), 1.93 (d, J = 21.6 Hz, 1H), 1.79 (d,J = 4.6 Hz, 1H), 1.62 (s, 2H), 1.25 (d, J = 6.5 Hz, 3H). LC-MS: [M + H]⁺= 493.0 93

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.25 (d, J = 3.4 Hz, 2H),7.58 (d, J = 12.7 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 7.13(t, J = 8.6 Hz, 1H), 5.83-5.52 (m, 2H), 3.90 (s, 3H), 3.41 (s, 2H), 3.04(d, J = 9.6 Hz, 3H), 2.91 (t, J = 11.3 Hz, 1H), 2.07-1.83 (m, 1H), 1.75(d, J = 15.2 Hz, 1H), 1.59 (t, J = 5.2 Hz, 2H), 1.20 (d, J = 6.2 Hz,3H). LC-MS: [M + H]⁺ = 506.8, 507.8. 94

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.24 (d, J = 9.4 Hz, 2H),7.59 (dd, J = 12.8, 2.2 Hz, 1H), 7.49 (dd, J = 8.5, 2.4 Hz, 1H), 7.29(s, 1H), 7.13 (t, J = 8.7 Hz, 1H), 5.85-5.44 (m, 2H), 3.90 (s, 3H), 3.38(s, 3H), 3.25 (q, J = 6.3 Hz, 1H), 3.06 (dd, J = 23.5, 11.4 Hz, 2H),2.96-2.70 (m, 2H), 1.92 (dd, J = 15.7, 9.1 Hz, 1H), 1.69 (tdd, J = 24.3,10.4, 6.2 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H). LC-MS: [M + H]⁺ = 506.8,507.8. 95

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 7.76(ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.55 (ddt, J = 8.0, 3.8, 1.7 Hz, 1H),7.37-7.26 (m, 2H), 5.73-5.61 (m, 2H), 3.47- 3.39 (m, 1H), 3.05 (d, J =8.1 Hz, 3H), 2.99- 2.87 (m, 1H), 1.91 (tt, J = 9.6, 4.8 Hz, 1H), 1.84-1.70 (m, 1H), 1.59 (dt, J = 10.4, 5.3 Hz, 2H), 1.20 (d, J = 6.3 Hz, 3H).LC-MS: [M + H]⁺ = 495.2. 96

¹H NMR (400 MHz, CD₃OD) δ 1.65-1.74 (2H, m), 1.79-1.91 (5H, m),2.73-2.83 (1H, m), 2.90- 3.00 (2H, m), 3.23-3.27 (1H, m), 3.75 (3H, s),3.77-3.78 (3H, m), 5.48-5.60 (2H, m), 6.96-7.05 (1H, m), 7.20 (1H, s),7.38 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8 Hz, 1.6 Hz), 8.14 (1H,d, J = 5.6 Hz), 8.37 (1H, s). LC-MS: [M + H]⁺ = 520.3. 97

¹H NMR (CD₃OD) δ: 8.50 (s, 1H), 8.24 (d, J = 4.8 Hz, 2H), 7.86-7.52 (m,2H), 7.46-7.12 (m, 2H), 5.88-5.49 (m, 2H), 3.38 (s, 3H), 3.30- 3.14 (m,2H), 3.15-2.65 (m, 4H), 2.06-1.47 (m, 4H), 1.18 (d, J = 6.4 Hz, 3H)LC-MS: [M + H]⁺ = 495.2 98

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H),7.72 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.54-7.44 (m, 1H), 7.33- 7.19 (m,2H), 5.65 (d, J = 2.3 Hz, 2H), 3.48 (d, J = 4.7 Hz, 1H), 3.16-2.97 (m,3H), 2.86 (t, J = 10.6 Hz, 1H), 2.11-1.88 (m, 2H), 1.81-1.57 (m, 3H),1.02 (dd, J = 18.3, 6.8 Hz, 6H). LC-MS: [M + H]⁺ = 509.3, 510.3. 99

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H),7.80-7.70 (m, 1H), 7.59-7.50 (m, 1H), 7.34 (s, 1H), 7.32-7.24 (m, 1H),5.64 (q, J = 12 Hz, 1H), 3.74-3.63 (m, 1H), 3.43-3.32 (m, 2H), 3.13-3.06(m, 1H), 3.05-2.98 (m, 1H), 2.95-2.87 (m, 1H), 2.86-2.75 (m, 1H),2.02-1.85 (m, 1H), 1.79-1.57 (m, 3H), 1.23-1.11 (m, 6H). LC-MS: [M + H]⁺= 509.2. 100

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.23 (d, J = 11.6 Hz, 2H), 7.75(ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.58-7.46 (m, 1H), 7.37-7.16 (m, 2H),5.65 (d, J = 2.9 Hz, 2H), 3.57-3.42 (m, 2H), 2.99 (h, J = 10.8, 9.9 Hz,3H), 2.10-1.94 (m, 2H), 1.94-1.79 (m, 3H), 1.79-1.57 (m, 7H). LC- MS:[M + H]⁺ = 533.3 101

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.24 (d, J = 13.6 Hz, 2H),7.74 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.53 (dddd, J = 8.8, 3.9, 2.3,1.4 Hz, 1H), 7.38-7.08 (m, 2H), 5.65 (s, 2H), 3.44 (d, J = 11.3 Hz, 1H),3.24(p, J = 6.8 Hz, 1H), 3.10-2.85 (m, 3H), 2.22-1.87 (m, 2H), 1.87-1.62(m, 3H), 1.39 (dt, J = 13.8, 7.0 Hz, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.90(t, J = 7.4 Hz, 3H). LC-MS: [M + H]⁺ = 521.3, 522.3. 102

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.24 (d, J = 15.4 Hz, 2H),7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.53 (ddt, J = 8.2, 3.4, 1.6 Hz,1H), 7.40-7.14 (m, 2H), 5.66 (s, 2H), 3.42 (d, J = 11.3 Hz, 1H), 3.23(q, J = 6.8 Hz, 1H), 3.12-2.90 (m, 3H), 2.12-1.94 (m, 2H), 1.87-1.78 (m,1H), 1.74-1.60(m, 2H), 1.39 (dp, J = 14.3, 7.3 Hz, 1H), 1.08 (d, J = 6.7Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). LC- MS: [M + H]⁺ = 521.3, 522.3. 103

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H),8.22 (s, 1H), 7.77-7.72 (m, 1H), 7.56-7.52 (m, 1H), 7.34-7.25 (m, 2H),5.72-5.61 (m, 2H), 3.46-3.38 (m, 1H), 3.06-2.92 (m, 3H), 2.62-2.54 (m,1H), 2.04-1.97 (m, 2H), 1.82-1.64 (m, 2H), 1.19 (t, J = 6.4 Hz, 3H),1.03- 0.95 (m, 1H), 0.58-0.38 (m, 2H), 0.31-0.17 (m, 2H). LC-MS: [M +H]⁺ = 533.1. 104

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (d, J = 4.3 Hz, 1H), 8.26 (s, 1H),8.22 (s, 1H), 7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.54 (ddt, J = 7.9,3.8, 1.7 Hz, 1H), 7.38-7.21 (m, 2H), 5.65 (s, 2H), 3.51-3.36 (m, 2H),3.01 (q, J = 12.6, 12.2 Hz, 3H), 2.13-1.92 (m, 2H), 1.85-1.67(m, 2H),1.10 (dd, J = 6.7, 4.1 Hz, 6H). LC-MS: [M + H]⁺ = 507.3, 508.3. 105

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.24 (d, J = 9.2 Hz, 2H),7.82-7.70 (m, 1H), 7.57-7.50 (m, 1H), 7.35-7.21 (m, 2H), 5.64 (s, 2H),4.06-3.87 (m, 1H), 3.40 (d, J = 11.2 Hz, 1H), 3.08-2.86 (m, 3H),2.38-2.24 (m, 2H), 2.19- 1.95 (m, 5H), 1.89-1.72 (m, 2H), 1.68-1.59 (m,1H). LC-MS: [M + H]⁺ = 519.1. 106

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H),8.23 (s, 1H), 7.80-7.69 (m, 1H), 7.58-7.49 (m, 1H), 7.37-7.23 (m, 2H),5.71-5.56 (m, 2H), 3.99-3.84 (m, 1H), 3.78-3.42 (m, 2H), 3.30-3.25 (m,3H), 3.08-2.91 (m, 3H), 2.32-1.60 (m, 10H). LC-MS: [M + H]⁺ = 563.1. 107

¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H),7.75-7.70 (m, 1H), 7.52-7.50 (m, 1H), 7.30 (s, 1H), 7.29-7.23 (m, 1H),5.70-5.60 (m, 2H), 3.45 (d, J = 11.6 Hz, 1H), 3.10-3.02 (m, 2H),2.90-2.85 (m, 1H), 2.12- 2.00 (m, 2H), 1.94-1.88 (m, 1H), 1.80-1.76 (m,1H), 1.60 (s, 3H), 1.28-1.12 (m, 2H), 0.67-0.60 (m, 2H). LC-MS: [M + H]⁺= 519.2. 108

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H),7.77-7.71 (m, 1H), 7.55-7.50 (m, 1H), 7.32-7.25 (m, 2H), 5.69-5.60 (m,2H), 3.99-3.92 (m, 2H), 3.55-3.41 (m, 4H), 3.05-2.93 (m, 3H), 2.10-1.94(m, 2H), 1.84-1.60 (m, 6H). LC-MS: [M + H]⁺ = 549.1. 109

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H),7.73 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.51 (ddt, J = 7.9, 3.8, 1.6 Hz,1H), 7.34-7.17 (m, 2H), 5.75-5.55 (m, 2H), 3.37 (d, J = 11.3 Hz, 1H),3.14-3.00 (m, 2H), 2.84 (td, J = 11.4, 2.9 Hz, 1H), 2.15-1.97 (m, 2H),1.88-1.78 (m, 1H), 1.74 (dq, J = 11.9, 3.2, 2.5 Hz, 1H), 1.34 (s, 9H).LC-MS: [M + H]⁺ = 521.3, 522.3. 110

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H),7.74-7.68 (m, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.50-7.47 (m, 1H),7.30-7.21 (m, 2H), 6.81 (d, J = 2.4 Hz, 1H), 5.50-5.35 (m, 2H), 3.99 (s,3H), 3.93-3.91 (m, 1H), 3.24-3.21 (m, 1H), 3.13-3.00 (m, 2H), 2.37- 2.31(m, 1H), 2.05-1.99 (m, 2H), 1.87-1.81 (m, 1H). LC-MS: [M + H]⁺ = 545.4.111

¹H NMR (CD₃OD) δ: 8.57-8.43 (m, 1H), 8.31- 8.06 (m, 2H), 7.78 (dddd, J =12.7, 7.5, 5.1, 2.2 Hz, 1H), 7.59 (ddd, J = 9.0, 4.4, 2.3 Hz, 1H),7.48-7.19 (m, 2H), 5.75-5.44 (m, 2H), 3.84 (ddd, J = 13.8, 11.2, 5.7 Hz,1H), 3.63-3.45 (m, 1H), 3.43-3.32 (m, 1H), 3.24 (dt, J = 12.6, 4.1 Hz,2H), 3.05-2.74 (m, 4H), 2.42-1.97 (m, 2H), 1.94-1.80 (m, 1H), 1.75-1.60(m, 2H), 1.58-1.37 (m, 1H) LC-MS: [M + H]⁺ = 535.3 112

¹H NMR (400 MHz, CD₃OD): δ 8.44 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H),7.79-7.67 (m, 1H), 7.57- 7.49 (m, 1H), 7.34-7.19 (m, 2H), 5.84-5.48 (m,2H), 3.82-3.67 (m, 2H), 3.54-3.43 (m, 1H), 3.30- 3.10 (m, 4H), 3.00-2.86(m, 1H), 2.12-1.81 (m, 4H), 1.13 (s, 3H). LC-MS: [M + H]⁺ = 535.0

Example 113 and Example 114:(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-oland(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)piperidin-3-yl)carbamate (Intermediate113-5) (1.2 g, 4.28 mmol) and methyl2-(3,4-difluorophenyl)-5-fluoroisonicotinate (Intermediate A) (1.144 g,4.28 mmol) in DMSO (30 mL) was added DIPEA (14.95 mL, 86 mmol) at rt,the reaction mixture was stirred at 120° C. for 8 hr under N₂atmosphere. The reaction mixture was diluted with water (40 mL),extracted with EtOAc (30 mL*3). The combined organic layers were washedwith water (20 mL*3), brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byflash chromatography (elution gradient: 10% to 50% EtOAc in PE in 40mins) to afford methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(113-6). LC-MS: [M+H]⁺=528.2.

To a solution of methyl5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)isonicotinate(113-6) (1.2 g, 2.275 mmol) in THF (30 mL) and MeOH (30 mL), was addedlithium chloride (1.929 g, 45.5 mmol) and sodium tetrahydroborate (1.721g, 45.5 mmol) at 0° C., the reaction mixture was stirred at rt for 4hours under N₂ atmosphere. The reaction mixture was diluted with 30 mlof water, extracted with EtOAc (20 mL*3). The combined organic layerswere washed with water (20 mL), brine (20 mL), concentrated to give acrude product. The crude product was purified by flash chromatography(elution gradient: 20% to 70% EtOAc in PE in 40 mins) to affordtert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(113-7). LC-MS: [M+H]⁺=500.2.

To a solution of tert-butyl(3-(2,2-difluoro-1-hydroxyethyl)-1-(6-(3,4-difluorophenyl)-4-(hydroxymethyl)pyridin-3-yl)piperidin-3-yl)carbamate(intermediate 113-7) (800 mg, 1.602 mmol), Intermediate B (645 mg, 1.922mmol) and triphenylphosphine (1260 mg, 4.80 mmol) in THF (20 mL), wasadded DEAD (0.761 mL, 4.80 mmol) dropwise at 0° C., after addition thereaction mixture was stirred at 0° C. for 0.5 hr under N₂ atmosphere.The reaction mixture was diluted with 20 ml of water, extracted withEtOAc (20 mL*3). The combined organic layers were washed with water (20mL), brine (20 mL), concentrated to give a crude product. The crudeproduct was purified by flash chromatography (elution gradient: 20% to70% EtOAc in PE in 50 mins) to afford tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(113-8). LC-MS: [M+H]⁺=817.2.

To a solution of tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(113-8) (600 mg, 0.735 mmol) in DCM (30 mL), was added TFA (10 mL), thereaction mixture was stirred at rt for 2 hr under N₂ atmosphere. Thereaction mixture was concentrated in vacuo to give the crude product.The crude product was purified by Pre-HPLC (Basic condition, NH3H2O%=0.05%, MEOH/H2O=0-95% in 10 mins) to afford 330 mg of pure racemicproduct. The racemic product was isolated by SFC to afford(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (Example 113) and(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol (Example 114).

Example 113: N H NMR (CD₃OD, 400 MHz) δ (ppm): 8.48 (M, 1H), 8.22 (d,2H), 7.71-7.77 (m, 1H), 7.51-7.54 (m, 1H), 7.29 (s, 13H), 7.24-7.27 (t,1H), 5.91-6.19 (t, 1H), 5.65 (m, 2H), 3.65 (br, 1H), 3.20 (d, 1H), 2.99(m, 2H), 2.84 (t, 1H), 1.93-1.99 (i, 1H), 1.66-1.86 (m, 3H). LC-MS:[M+H]⁺=517.2.

Example 114:1 H NMR (CD₃OD-d6, 400M Hz) δ (ppm): 8.49 (s, 1H), 8.22 (d,2H), 7.69-7.75 (m, 1H), 7.48-7.51 (m, 1H), 7.24-7.31 (t, 1H), 7.21 (s,1H)), 5.89-6.18 (t, 1H), 5.65 (s, 2H), 3.95 (br, 1H), 3.25 (d, 1H),2.90-3.10 (b, 3H), 1.82-1.88 (m, 3H), 1.63 (br, 1H). LC-MS: [M+H]-517.2.

Example 115-155 can be prepared following procedures analogous to thosedescribed in Example 113 and 114.

Example # Structure ¹H NMR & MS 115

¹H NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H), 8.23-8.20 (d, J = 104 Hz, 2H),7.38-7.30 (m, 3H), 6.86-6.58 (m, 2H), 6.22-5.93 (m, 1H), 5.70 (s, 2H),3.73-3.68 (m, 1H), 3.26-3.23 (m, 1H), 3.15-3.05 (m, 2H), 2.92-2.86 (m,1H), 2.11 (s, 3H),2.03-2.01 (m, 1H), 1.89- 1.70 (m, 3H). LC-MS: [M + H]⁺= 545.4. 116

¹H NMR (400 MHz, CD₃OD) δ ppm 8.43 (s, 1H), 8.17 (d, J = 14.2 Hz, 2H),7.81-7.39 (m, 2H), 7.31-7.11 (m, 2H), 6.80 (t, J = 73.3 Hz, 1H), 5.98(td, J = 55.4, 4.4 Hz,1H), 5.60(s,2H), 3.90 (s, 1H), 3.17 (d,J = 11.3Hz,1H), 3.02-2.79 (m,3H), 1.92- 1.51(m,4H). LC-MS: [M + H]⁺ = 565.2,566.2. 117

¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1H), 8.25(s, 1H), 8.22 (s, 1H), 7.15(dt, J = 8.0, 11.2 Hz, 2H), 6.80 (s, 1H), 6.26-5.92 (m, 1H), 5.70 (s,2H), 3.83-3.65 (m, 1H), 3.29-3.21 (m, 1H), 3.19-3.05 (m, 2H), 2.97-2.83(m, 1H), 2.11-2.05 (m, 1H), 2.03 (s, 3H), 1.94- 1.80 (m, 2H), 1.78-1.69(m, 1H). LC-MS: [M + H]⁺ = 531.4. 118

¹H NMR (400 MHz, CD₃OD) δ = 8.37 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H),7.75 (ddd, J = 2.1, 7.9, 11.6 Hz, 1H), 7.67 (br d, J = 5.9 Hz, 1H),7.42-7.31 (m, 1H), 6.18-5.84 (m, 1H), 5.62 (q, J = 14.1 Hz, 2H), 3.82(br s, 1H), 3.37 (s, 3H), 3.20-3.11 (m, 1H), 2.99 (br d, J = 9.8 Hz,1H), 2.94-2.87 (m, 1H), 2.85-2.76 (m, 1H), 1.91- 1.60 (m, 4H). LC-MS:[M + H]⁺ = 547.5. 119

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.24 (d, J = 7.9 Hz, 2H),7.85-7.44 (m, 2H), 7.41-7.18 (m, 2H), 6.86 (t, J = 73.3 Hz, 1H), 6.05(td, J = 55.1, 3.9 Hz, 1H), 5.65 (s, 2H), 3.67 (dd, J = 16.5, 6.6 Hz,1H), 3.22 (d, J = 11.4 Hz, 1H), 3.02 (t, J = 13.5 Hz, 2H), 2.91-2.79 (m,1H), 2.09-1.91 (m, 1H), 1.89- 1.62 (m, 3H). LC-MS: [M + H]⁺ = 565.2,566.2. 120

¹H NMR (400 MHz, CD₃OD) δ = 8.57 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H),7.74 (br dd, J = 5.9, 10.7 Hz, 1H), 7.35 (dd, J = 5.6, 10.7 Hz, 1H),7.16 (s, 1H), 7.12-6.79 (m, 1H), 6.23-5.88 (m, 1H), 5.69 (s, 2H), 3.99(br s, 1H), 3.27 (br s, 1H), 3.16-2.90 (m, 3H), 2.03-1.79 (m, 3H), 1.66(br s, 1H). LC-MS: [M + H]⁺ = 567.4. 121

¹H NMR (400 MHz, CD₃OD) δ ppm 8.43 (s, 1H), 8.24(d, J = 2.1 Hz, 2H),7.82 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.6 Hz, 1H), 7.24 (s, 1H),7.08 (d, J = 8.7 Hz, 1H), 6.23-5.86 (m, 1H), 5.64 (s, 2H), 3.89 (s, 3H),3.74-3.61 (m, 1H), 3.20 (br d, J = 11.5 Hz, 1H), 3.07-2.94 (m, 2H), 2.88= 275 (m, 1H), 2.04-1.90 (m, 1H), 1.88-1.60 (m, 3H).LC-MS: [M + H]⁺ =545.4. 122

¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.24 (d, 2H), 7.93 (t , 1H),7.65-7.7.68 (m, 1H), 7.32 (s, H), 7.24 (t, H)-5.90-6.19 (t, 1H), 5.64(s, 2H), 3.65 (br, 1H), 3.2 (d, 1H), 3.00 (m, 2H), 2.83 (t, 1H), 1.97(m, 1H), 1.66-1.86 (m, 3H). LC-MS: [M + H]⁺ = 532.9, 533.9. 123

¹H NMR (400 MHz, CD₃OD) δ = 8.51 (s, 1H), 8.22 (d, J = 3.7 Hz, 2H),8.10-7.97 (m, 2H), 7.31 (d, J = 11.5 Hz, 1H), 7.10(d, J = 1.8 Hz, 1H),6.27-5.90 (m, 1H), 5.69 (s, 2H), 4.01 (s, 3H), 3.78- 3.64(m, 1H), 3.24(br d, J = 11.5 Hz, 1H), 3.13 (br d, J = 10.9 Hz, 1H), 3.05 (br d, J =11.4 Hz, 1H), 2.89 (br t, J = 10.3 Hz, 1H), 2.09-1.96 (m, 1H), 1.92-1.76 (m, 2H), 1.70 (br d, J = 10.4 Hz, 1H). LC-MS: [M + H]⁺ = 553.5. 124

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.24-8.23 (d, J = 6.0 Hz,2H), 7.74-7.71 (m, 1H), 7.56-7.54 (m, 1H), 7.51-7.49 (m, 1H), 7.36 (s,1H), 6.19-5.91 (m, 1H), 5.66 (s, 2H), 3.70-3.65 (m, 1H), 3.23-3.21 (d, J= 11.6 Hz, 1H), 3.07-3.00 (m, 2H), 2.87-2.82 (m, 1H), 2.01-1.98 (m, 1H),1.86-1.70 (m, 3H).LC- MS: [M + H]⁺ = 533.4. 125

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.23(d, J = 8.8 Hz, 2H),7.80 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 2.1, 8.6 Hz, 1H), 7.15 (s, 1H),7.07 (d, J = 8.7 Hz, 1H), 6.22-5.86 (m, 1H), 5.65 (s, 2H), 4.05-3.85 (m,4H), 3.21 (br d, J = 11.0 Hz, 1H), 3.05-2.90 (m, 3H), 1.96- 1.72 (m,3H), 1.71-1.56 (m, 1H). LC-MS: [M + H]⁺ = 545.4. 126

¹H NMR (400 MHz,CD₃OD): δ 8.44 (s, 1H), 8.22-8.17 (d, J = 7.6 Hz, 2H),7.08-7.00 (m, 3H), 6.72 (s, 1H), 6.22-5.93 (m, 1H), 5.68 (s, 2H), 3.71(m, 1H), 3.25-3.22 (m, 1H), 3.13-3.04 (m, 2H), 2.90-2.85 (m, 1H), 2.29(s, 3H), 2.11-2.09 (m, 1H), 2.01 (s, 3H), 1.89-1.70 (m, 3H). LC-MS: [M +H]⁺ = 509.4 127

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.23 (d, J = 9.2 Hz, 2H),7.54 (dd, J = 12.7, 2.2 Hz, 1H), 7.43 (dd, J = 8.7, 1.6 Hz, 1H), 7.11(dd, J = 17.6, 9.0 Hz, 2H), 6.04 (td, J = 55.4, 4.5 Hz, 1H), 5.65 (s,2H), 3.95 (s, 1H), 3.88 (s, 3H), 3.22 (d, J = 11.0 Hz, 1H), 2.96 (d, J =15.1 Hz, 3H), 1.86 (d, J = 13.5 Hz, 3H), 1.64 (s, 1H). LC-MS: [M + H]⁺ =529.0, 530.0. 128

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1H), 8.26 (s, 1H), 8.11 (s,1H), 7.83 (dd, J = 11.5, 7.2 Hz, 1H), 7.52-7.04 (m, 4H), 6.98 (d, J =1.6 Hz, 1H), 6.18 (td, J = 55.8, 4.0 Hz, 1H), 5.72(s, 1H), 5.56(d, J =2.4 Hz, 2H), 3.77 (s, 1H), 3.08 (dd, J = 30.6, 8.8 Hz, 2H), 2.93 (t, J =9.6 Hz, 1H), 2.79 (d, J = 11.3 Hz, 1H), 1.80 (q, J = 27.0, 21.6 Hz, 5H),1.48 (d, J = 9.8 Hz, 1H). LC-MS: [M + H]⁺ = 582.9, 583.8. 129

¹H NMR (400 MHz, CD₃OD) δ = 8.50 (s, 1H), 8.23 (s, 1H), 8.20-8.14 (m,1H), 7.42 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 10.8 Hz, 1H), 7.07- 6.75 (m,2H), 6.24-5.90 (m, 1H), 5.69 (s, 2H), 3.70 (ddd, J = 4.1, 8.3, 12.2 Hz,1H), 3.24 (d, J = 11.5 Hz, 1H), 3.13 (br d, J = 11.4 Hz, 1H), 3.06 (brd, J = 11.4 Hz, 1H), 2.94-2.84 (m, 1H), 2.06 (s, 3H), 2.04-1.98 (m, 1H),1.91-1.77 (m, 2H), 1.72 (br d, J = 15.3 Hz, 1H) . LC-MS: [M + H]⁺ =563.4. 130

¹H NMR (400 MHz, CD₃OD) δ ppm 8.29 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H),6.68 (s, 1H), 6.03 (td, J = 55.1, 3.9 Hz, 1H), 5.71-5.33 (m, 2H), 3.65(d, J = 15.2 Hz, 1H), 3.15 (d, J = 11.4 Hz,1H), 2.95 (dd, J = 19.0, 11.6Hz, 2H), 2.78(t, J = 10.6 Hz, 1H), 2.62-2.48 (m, 1H), 1.95 (q, J = 11.3,10.8 Hz, 1H), 1.74(d, J = 18.8 Hz, 7H), 1.40- 1.24 (m, 5H), 1.22-0.84(m, 1H). LC-MS: [M + H]⁺ = 487.3, 488.3. 131

¹H NMR (400 MHz, CD₃OD) δ ppm 8.44 (s, 1H), 8.23 (d, J = 1.9 Hz, 2H),7.56 (dd, J = 12.7, 2.2 Hz, 1H), 7.45 (ddd, J = 8.6, 2.3, 1.2 Hz, 1H),7.24 (s, 1H), 7.10 (t, J = 8.7 Hz, 1H), 6.05 (td, J = 55.1, 3.9 Hz, 1H),5.64 (d, J = 2.6 Hz, 2H), 3.75- 3.60 (m, 1H), 3.20 (d, J = 11.4 Hz, 1H),3.00 (t, J = 13.6 Hz, 2H), 2.88-2.75 (m, 1H), 1.97 (d, J = 12.3 Hz, 1H),1.88-1.61 (m, 3H). LC-MS: [M + H]⁺ = 529.0, 530.0. 132

¹H NMR (400 MHz, CD₃OD) δ = 8.54 (d, J = 1 .6 Hz, 1H), 8.22 (s, 1H),8.21 (s, 1H), 7.92-7.84 (m, 1H), 7.45-7.36 (m, 1H), 7.33-7.25 (m, 1H),7.18 (s, 1H), 6.94-6.60 (m, 1H), 6.23- 5.92 (m, 1H), 5.68 (s, 2H),3.79-3.64 (m, 1H), 3.28-3.21 (m, 1H), 3.18-3.03 (m, 2H), 2.94- 2.83(m,1H),2.11-1.97(m, 1H), 1.93-1.67 (m, 3H). LC-MS: [M + H]⁺ = 549.5. 133

¹H NMR (400 MHz, CD₃OD) δ ppm 8.42 (s, 1H), 8.11 (d, J = 4.3 Hz, 2H),7.78 (t, J = 8.4 Hz, 1H), 7.23-7.07 (m, 2H), 7.02 (s, 1H), 6.15- 5.80(m, 1H), 5.58 (s, 2H), 3.68-3.50 (m, 1H), 3.25(s, 1H), 3.14 (d, J = 11.4Hz, 1H), 3.03 (d, J = 10.9 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 2.83-2.64 (m, 1H), 2.01-1.82 (m, 1H), 1.91-1.63 (m, 3H).LC-MS: [M + H]⁺ =533.4. 134

¹H NMR (400 MHz, CD₃OD) δ = 8.58 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H),7.80-7.70 (m, 1H), 7.40-7.32 (m, 1H), 7.27 (s, 1H), 7.13-6.80 (m, 1H),6.26-5.94 (m, 1H), 5.77-5.61 (m, 2H), 3.85-3.72 (m, 1H), 3.28-3.09 (m,3H), 2.97-2.86 (m, 1H), 2.10-2.00 (m, 1H), 1.97- 1.80 (m, 3H) LC-MS:[M + H]⁺ = 567.4, 135

¹H NMR (400 MHz, CD₃OD) δ = 8.39 (s, 1H), 8.24 (s, 1H), 8.10 (d, J = 2.0Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 6.87 (dd, J = 2.4, 8.6 Hz, 1H), 6.79(dd, J = 2.4, 12.2 Hz, 1H), 6.21-5.88 (m, 1H), 5.77-5.58 (m, 2H),3.97-3.77 (m, 4H), 3.25- 3.17 (m, 1H), 3.15-3.06 (m, 1H), 3.05-2.96 (m,1H), 2.95-2.85 (m, 1H), 2.01-1.87 (m, 1H), 1.86- 1.66 (m, 3H).). LC-MS:[M + H]⁺ = 547.5. 136

¹H NMR (400 MHz, CD₃OD): δ 8.54 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H),8.23-8.21 (m, 1H), 7.00-6.85 (m, 3H), 6.27-5.93 (m, 1H), 5.71 (s, 2H),3.84-3.67 (m, 1H), 3.31-3.25 (m, 1H), 3.21-3.15 (m, 1H), 3.14-3.08 (m,1H), 2.97-2.88 (m, 1H), 2.14-2.02 (m, 1H), 1.96- 1.81 (m, 2H), 1.81-1.72(m, 1H). LC-MS: [M + H]⁺ = 549.4. 137

¹H NMR (400 MHz, CD₃OD): δ 8.57 (s, 1H), 8.30-8.20 (m, 2H), 7.92 (t, J =8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 11.2 Hz, 1H), 7.13(s, 1H), 6.98-6.64 (m, 1H), 6.26-5.92 (m, 1H), 5.72 (s, 2H), 4.17-3.93(m, 1H), 3.32-3.24 (m, 1H), 3.16-2.94 (m, 3H), 2.06-1.82 (m, 3H),1.75-1.59 (m, 1H). LC-MS: [M + H]⁺ = 549.4. 138

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.21 (d, J = 2.2 Hz, 2H),7.81 (t, J = 8.8 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 7.08-6.71 (m, 3H),6.06 (td, J = 55.1, 3.9 Hz, 1H), 5.68 (s, 2H), 3.70 (dd, J = 15.8, 8.2Hz, 1H), 3.23 (d, J = 11.4 Hz, 1H), 3.12 (d, J = 11.1 Hz, 1H), 3.04 (d,J = 11.4 Hz, 1H), 2.88 (t, J = 10.6 Hz, 1H), 2.02 (t, J = 11.6 Hz, 1H),1.91-1.75 (m, 2H), 1.70 (d, J = 13.5 Hz, 1H). LC-MS: [M + H]⁺ = 565.2,566.2. 139

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.21-8.24 (d, 2H), 7.91-7.93(t, 1H), 7.65 (br, 1H), 7.22-7.28 (br, 2H), 5.89-6.18 (t, 1H), 5.65 (s,2H), 3.94 (br, 1H), 3.25 (d, 1H), 2.95 (b, 3H), 1.88 (m, 3H), 1.63 (m,1H). LC- MS: [M + H]⁺ = 532.9, 533.9. 140

¹H NMR: (400 MHz, CD₃CN): δ 8.51 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H),7.40-7.34 (m, 3H), 6.91-6.59 (m, 2H), 6.19-5.87 (m, 3H), 5.54 (s, 2H),3.80 (m, 1H), 3.14 (m, 1H), 3.07-2.98 (m, 1H), 2.90 (m, 2H), 2.11 (s,3H), 2.09 (m, 1H), 1.84- 1.71 (m, 2H), 1.62-1.50 (m, 1H). LC-MS: [M +H]⁺ = 545.5. 141

¹H NMR (400 MHz, CD₃OD): δ 8.56 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H),8.02-7.98 (m, 1H), 7.56-7.54 (d, J = 8.0 Hz, 1H), 7.48-7.45 (d, J = 11.2Hz, 1H), 7.21 (s, 1H), 6.22-5.93 (m, 1H), 5.69 (s, 2H), 3.73-3.67 (m,1H), 3.27-3.24 (d, J = 11.6 Hz, 1H), 3.16-3.14 (m, 1H), 3.09-3.06 (d, J= 11.2 Hz, 1H), 2.92-2.87 (m, 1H), 2.07-2.02 (m, 1H), 1.89-1.79 (m, 2H),1.74-1.70 (m, 1H). LC-MS: [M + H]⁺ = 567.4. 142

¹H NMR (400 MHz, CD₃OD) δ = 8.52 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H),8.17 (d, J = 2.4 Hz, 1H), 7.58 (dt, J = 6.5, 8.5 Hz, 1H), 7.17-7.04 (m,2H), 6.31-5.98 (m, 1H), 5.76-5.57 (m, 2H), 4.08- 3.91 (m, 1H), 3.46-3.35(m, 1H), 3.30-3.25 (m, 1H), 3.16-3.06(m, 1H), 3.06-2.94 (m, 1H), 2.11-1.82 (m, 4H). LC-MS: [M + H]⁺ = 535.4. 143

¹H NMR (400 MHz, CD₃OD) δ = 8.52 (s, 1H), 8.24 (s, 1H), 8.20 (s, 1H),8.07-8.03 (m, 2H), 7.31 (d, J = 11.5 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H),6.24-5.88 (m, 1H), 5.74-5.67 (m, 2H), 4.01 (s, 3H), 3.23-3.29 (m, 1H),3.16-2.91 (m, 3H), 2.20-2.15 (m, 1H), 1.93-1.80 (m, 3H), 1.74-1.57 (m,1H). LC-MS: [M + H]⁺ = 553.4. 144

¹H NMR (400 MHz, CD₃OD) δ = 8.45 (s, 1H), 8.20 (d, J = 9.6 Hz, 2H), 7.50(m, 1H), 7.04 (s, 1H), 6.58 (m, 1H) , 6.20-5.92 (m, 1H), 5.65 (s, 2H),4.0 (s, 1H), 3.26-3.23 (m, 1H), 3.01- 2.99 (m, 3H), 1.91-1.88 (m, 3H),1.70 (br s, 1H). LC-MS: [M + H]⁺ = 533.3. 145

¹H NMR (400 MHz, CD₃OD) δ ppm 8.29 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H),6.59 (s, 1H), 6.03 (td, J = 55.4, 4.3 Hz, 1H), 5.61 (s, 2H), 3.95(s,1H), 3.19-3.11 (m, 1H), 2.91 (d, J = 18.5 Hz, 3H), 2.62-2.45 (m, 1H),1.89-1.61 (m, 9H), 1.36-1.22 (m, 5H). LC-MS: [M + H]⁺ = 487.3, 488.3.146

¹H NMR (400 MHz, CD₃OD) δ = 8.56 (s, 1H), 8.23 (d, J = 10.0 Hz, 2H),7.70 (t, J = 7.4 Hz, 1H), 7.43 (br t, J = 7.2 Hz, 1H), 7.19 (d, J = 1.0Hz, 1H), 7.16-6.85 (m, 1H), 6.24-5.91 (m, 1H), 5.70 (s, 2H), 3.78-3.63(m, 1H), 3.26 (m, 1H), 3.19- 3.04 (m, 2H), 2.95-2.85 (m, 1H), 2.14-1.98(m, 1H), 1.93-1.65 (m, 1H), 1.93-1.65 (m, 3H). LC- MS: [M + H]⁺ = 567.4.147

¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H), 8.21 (d, J = 15.3 Hz, 2H), 7.78(td, J = 8.8, 6.5 Hz, 1H), 7.15-6.70 (m, 3H), 6.05 (td, J = 55.4, 4.4Hz, 1H), 5.69 (s, 2H), 3.99 (s, 1H), 3.15-2.81 (m, 3H), 1.89 (d, J =16.2 Hz, 3H), 1.65 (s, 1H). LC-MS: [M + H]⁺ = 517.2, 518.2. 148

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.21 (d, J = 13.9 Hz, 2H),7.77 (t, J = 8.4 Hz, 1H), 7.31-7.16 (m, 2H), 7.05 (s, 1H), 6.24-5.88 (m,1H), 5.69 (s, 2H), 4.11-3.88 (m, 1H), 3.26 (m, 1H), 3.16-2.90 (m, 3H),1.90 (m, 3H), 1.67 (m, 1H). LC-MS: [M + H]⁺ = 533.4. 149

¹H NMR (400 MHz, CD₃OD) δ = 8.40 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H),7.28 (dd, J = 6.7, 11.3 Hz, 1H), 7.01 (dd, J = 7.1, 11.4 Hz, 1H),6.23-5.88 (m, 1H), 5.76-5.56 (m, 2H), 4.0- 3.80 (m, 4H), 3.26-3.18 (m,1H), 3.18-3.08 (m, 1H), 3.08-2.97 (m, 1H), 2.97-2.84 (m, 1H), 2.06-1.88(m, 1H), 1.88-1.66 (m, 3H) LCMS: [M + H]⁺ = 565.4 150

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.52 (s, 1H), 8.26 (s, 1H), 8.11 (s,1H), 7.83 (dd, J = 11.5, 7.2 Hz, 1H), 7.56-7.07 (m, 4H), 7.02 (d, J =1.6 Hz, 1H), 6.19 (td, J = 55.4, 3.1 Hz, 1H), 5.62 (s, 1H), 5.58 (s,2H), 3.54 (dd, J = 17.7, 9.3 Hz, 1H), 3.09 (d, J = 11.4 Hz, 2H),2.94-2.75 (m, 2H), 1.98(d, J = 12.5 Hz, 3H), 1.76-1.64 (m, 2H), 1.54 (d,J = 12.8 Hz, 1H).LC-MS: [M + H]⁺ = 582.9, 583.8. 151

¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H), 8.21 (d, J = 15.4 Hz, 2H), 7.78(td, J = 8.9, 6.6 Hz, 1H), 7.09-6.87 (m, 3H), 6.05 (td, J = 55.4, 4.5Hz, 1H), 5.69 (s, 2H), 3.99 (s, 1H), 3.25 (d, J = 1.9 Hz, 1H), 3.12-2.83(m, 3H), 2.02-1.77 (m, 3H), 1.65 (s, 1H). LC-MS: [M + H]⁺ = 517.2,518.2. 152

¹HNMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.25-8.22 (d, J = 10.8 Hz,2H), 7.72-7.69 (m, 1H), 7.54-7.49 (m, 2H), 7.27 (s, 1H), 6.18- 5.90 (m,1H), 5.66 (s, 2H), 3.95 (m, 1H), 3.24- 3.22 (d, J = 11.2 Hz, 1H), 2.98(m, 3H), 1.89- 1.83 (m, 3H), 1.66 (m, 1H). LC-MS: [M + H]⁺ = 533.4. 153

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.21 (d, J = 10.4 Hz, 2H),7.80 (t, J = 8.8 Hz, 1H), 7.12-6.67 (m, 4H), 6.05 (td, J = 55.5, 4.4 Hz,1H), 5.68 (s, 2H), 3.99 (s, 1H), 3.26 (d, J = 11.5 Hz, 1H), 3.00 (dd, J= 29.4, 14.5 Hz, 3H), 1.89 (d, J = 13.5 Hz, 3H), 1.65 (s, 1H). LC-MS:[M + H]⁺ = 565.2, 566.2. 154

¹H NMR (400 MHz, CD₃OD) δ = 8.59 (s, 1H), 8.35-8.25 (m, 1H), 8.21 (s,1H), 7.80-7.70 1H), 7.40-7.31 (m, 1H), 7.30-7.20 (m, 1H), 7.12-6.78 (m,1H), 6.32-5.88 (m, 1H), 5.82-5.58 (m, 2H), 3.97-3.80 (m, 1H), 3.33- 3.32(m, 1H), 3.21-3.10 (m, 1H), 3.00-2.80 (m, 1H), 2.18-1.79 (m, 4H) LC-MS:[M + H]⁺ = 567.4, 155

¹H NMR (400 MHz, CD₃OD) δ = 8.50 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.31(dd, J = 4.6, 8.9 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 7.76 (s, 1H),7.65 (dt, J = 2.9, 8.6 Hz, 1H), 6.24-5.93 (m, 1H), 5.70 (s, 2H),3.78-3.63 (m, 1H), 3.26 (d, J = 11.5 Hz, 1H), 3.18-3.12 (m, 1H),3.10-3.04 (m, 1H), 2.96-2.84 (m, 1H), 2.14-1.98(m, 1H), 1.93-1.76 (m,2H), 1.76- 1.65 (m, 1H). LC-MS: [M + H]⁺ = 500.2.

Example 156 and Example 157:(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-01and (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

Step 1. To a solution of1-(3-amino-1-(4-(hydroxymethyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Intermediate 156-2) (700 mg, 1.677 mmol, 1.0 eq), Intermediate B (80mg, 0.240 mmol, 1.5 eq) and n-Bu₃P (509 mg, 2.516 mmol, 1.5 eq) inanhydrous THF (7 mL) was added DIAD (509 mg, 2.516 mmol, 1.5 eq) undernitrogen at 0° C. The reaction mixture was stirred at 0° C. for 30 min.The reaction mixture was concentrated in vacuum and the residue waspurified by Prep-HPLC (base) to give Intermediate 156-3. ¹H NMR (400MHz, CDCl₃) δ=8.93-8.85 (m, 1H), 8.57 (s, 1H), 8.22-8.14 (m, 1H),7.92-7.76 (m, 1H), 7.45-7.32 (m, 1H), 7.01-6.83 (m, 1H), 6.20-5.80 (m,1H), 5.72-5.53 (m, 2H), 3.82-3.63 (m, 1H), 3.26-3.06 (m, 2H), 3.05-2.89(m, 2H), 2.28-2.12 (m, 1H), 1.89-1.79 (m, 2H), 1.75-1.63 (m, 1H),1.49-1.36 (m, 18H). LCMS: [M+H]⁺=735.5.

Step 2. To a solution of Intermediate 156-3 (630 mg, 0.858 mmol) inanhydrous DCM (15 mL) was added TFA (5 mL) and the reaction was stirredat 20° C. for 3 hours. The reaction mixture was concentrated in vacuumand basified with ammonium hydroxide to pH=8, concentrated in vacuum.The residue was purified by Prep-HPLC (base) and SFC to give(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 156) and(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 157).

Example 156: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (d, J=1.9 Hz, 1H), 8.20(dd, J=5.6, 2.0 Hz, 2H), 7.78 (dddd, J=11.4, 9.2, 7.1, 2.0 Hz, 1H),7.42-7.05 (m, 2H), 6.35-5.80 (m, 1H), 5.67 (d, J=2.0 Hz, 2H), 3.68 (d,J=14.0 Hz, 1H), 3.22 (s, 1H), 3.14-3.00 (m, 2H), 2.88 (t, J=11.2 Hz,1H), 2.03 (t, J=11.5 Hz, 1H), 1.82 (t, J=12.9 Hz, 2H), 1.71 (d, J=13.0Hz, 1H). LC-MS: [M+H]+=535.2.

Example 157: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.25 (s, 1H),8.21 (s, 1H), 7.87-7.74 (m, 1H), 7.25-7.15 (m, 1H), 7.09 (s, 1H),6.26-5.88 (m, 1H), 5.70 (s, 2H), 4.10-3.90 (m, 1H), 3.30-3.20 (m, 1H),3.17-2.87 (m, 3H), 2.03-1.80 (m, 3H), 1.75-1.60 (m, 1H). LC-MS:[M+H]+=535.4.

Examples 158 and 159 were prepared following procedures analogous to thepreparation of Examples 156 and 157 (Step 2).

Example No. ¹H NMR 158

  or ¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.20 (d, J = 2.5 Hz,2H), 7.47-7.34 (m, 2H), 7.27 (td, J = 8.5, 2.5 Hz, 1H), 7.01- 6.63 (m,2H), 6.06 (td, J = 55.1, 3.8 Hz, 1H), 5.68 (s, 2H), 3.78-3.57 (m, 1H),3.23 (d, J = 11.5 Hz, 1H), 3.12(d, J = 11.3 Hz, 1H), 3.05 (d, J = 11.5Hz, 1H), 2.88 (t, J = 10.8 Hz, 1H), 2.02 (dd, J = 13.6, 9.3 Hz, 1H),1.83 (td, J = 14.9, 13.8, 6.8 Hz, 2H), 1.71 (d, J = 14.7 Hz, 1H). LC-MS:[M + H]⁺ = 549.2. 159

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.20 (d, J = 8.5 Hz, 2H),7.46-7.33 (m, 2H), 7.27 (td, J = 8.5, 2.6 Hz, 1H), 6.98- 6.62 (m, 2H),3.98 (s, 1H), 3.25 (s, 1H), 3.02 (dt, J = 27.3, 9.5 Hz, 3H), 1.89 (d, J= 15.4 Hz, 3H), 1.65 (s, 1H). LC-MS: [M + H]⁺ = 549.2.

Example 160 and Example 161:(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-oland(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

To a solution of tert-butyl(tert-butoxycarbonyl)(9-((5-(3-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(2,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(Intermediate 160-3) (200 mg, 0.237 mmol) in DCM (18 mL), was added TFA(36 mL), and the reaction mixture was stirred at rt for 30 min under N₂atmosphere. The reaction mixture was concentrated in vacuo to give thecrude product. The crude product was purified by Pre-HPLC and SFC toafford(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 160) and(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 161).

Example 160: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.20 (d, J=1.6Hz, 2H), 7.58 (dd, J=12.2, 7.3 Hz, 1H), 7.11 (d, J=1.3 Hz, 1H), 6.90(dd, J=12.6, 7.1 Hz, 1H), 6.06 (td, J=55.1, 3.9 Hz, 1H), 5.67 (s, 2H),3.87 (s, 3H), 3.75-3.58 (m, 1H), 3.25-2.75 (m, 4H), 2.26-1.60 (m, 4H).LC-MS: [M+H]⁺=547.2, 548.2.

Example 161: ¹H NMR (400 MHz, CD₃OD) δ=8.51-8.44 (m, 1H), 8.24-8.16 (m,2H), 7.62-7.48 (m, 1H), 7.03 (s, 1H), 6.93-6.79 (m, 1H), 6.25-5.86 (m,1H), 5.71-5.59 (m, 2H), 4.00 (m, 1H), 3.88-3.80 (m, 3H), 3.28-2.87 (m,4H), 1.99-1.56 (m, 4H). LC-MS: [M+H]⁺=547.4.

Example 162 and Example 163:(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-oland(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol

To a solution of intermediate 162-2 (57 mg, 0.129 mmol) Intermediate B(43.1 mg, 0.129 mmol) and PPh₃ (101 mg, 0.386 mmol) in THF (5 mL) wasadded DEAD (0.061 mL, 0.386 mmol). The reaction mixture was stirred at0° C. for 30 min under N₂ atmosphere. The reaction mixture was quenchedwith water and extracted with EtOAc, the combined organic phase waswashed with water, brine, dried over sodium sulfate, concentrated togive a crude product. The crude product was purified by flashchromatography (elution gradient: 0% to 10% MeOH in DCM in 30 mins) toafford the intermediate. LC-MS: [M+H]⁺=761.

To a solution of the intermediate (200 mg, 0.263 mmol) in DCM (18 mL)was added TFA (36 mL, 467 mmol), the reaction mixture was stirred at rtfor 30 min under N₂ atmosphere. The crude product was purified byPre-HPLC (Basic condition, NH₃H₂O %=0.05%, MeOH/H₂O=0-95% in 10 mins) toafford the pure product, and then further purified by to afford(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 162) and(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol(Example 163).

Example 162: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.21 (d, J=3.7Hz, 2H), 7.34-7.26 (m, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.07 (dt, J=8.6, 1.8Hz, 1H), 6.95-6.61 (m, 2H), 6.07 (td, J=55.1, 3.9 Hz, 1H), 5.68 (s, 2H),3.76-3.61 (m, 1H), 3.22 (d, J=11.4 Hz, 1H), 3.17-3.08 (m, 1H), 3.04 (d,J=11.4 Hz, 1H), 2.93-2.81 (m, 1H), 2.02 (dd, J=13.9, 8.9 Hz, 1H),1.91-1.75 (m, 2H), 1.70 (d, J=12.7 Hz, 1H). LC-MS: [M+H]+=560.9, 562.0.

Example 163: ¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.30 (d, J=14.6Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (dd,J=8.6, 2.6 Hz, 1H), 7.01 (s, 1H), 6.85 (t, J=55.3 Hz, 1H), 6.19 (td,J=53.9, 2.6 Hz, 1H), 5.68 (d, J=3.3 Hz, 2H), 4.20 (s, 1H), 3.50-3.34 (m,2H), 3.19-2.98 (m, 2H), 2.02 (d, J=42.5 Hz, 4H). LC-MS: [M+H]+=560.9,562.0.

Examples 164-167 were prepared from Intermediate B and correspondingintermediates following procedures analogous to the preparation ofExamples 162 and 163.

Example No. Intermediate LC-MS and/or ¹H NMR 164

  or

  164-2 1H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.23 (d, J = 6.6 Hz,2H), 7.56-7.37 (m, 2H), 7.32 (s, 1H), 6.05 (td, J = 55.1, 3.9 Hz, 1H),5.64 (d, J = 2.0 Hz, 2H), 3.97 (d, J = 1.1 Hz, 3H), 3.66 (ddd, J = 16.7,8.5, 3.6 Hz, 1H), 3.20 (d, J = 11.4 Hz, 1H), 3.09-2.89 (m, 2H), 2.82(td, J = 11.1, 2.7 Hz, 1H), 2.10-1.86 (m, 1H), 1.85-1.58 (m, 3H). LC-MS:[M + H]⁺ = 547.2, 548.2 165

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.23(d, J = 11.8 Hz, 2H),7.41 (d, J = 9.3 Hz, 2H), 7.22 (s, 1H), 6.03 (td, J = 55.5, 4.5 Hz, 1H),5.64(s, 2H), 3.97 (s, 4H), 3.22 (d, J = 11.1 Hz, 1H), 3.05- 2.92 (m,3H), 1.84 (d, J = 22.8 Hz, 3H), 1.63 (s, 1H). LC-MS: [M + H]⁺ = 547.2,548.2 166

  or

  166-2 ¹H NMR (400 MHz, CD₃OD) δ ppnn 8.64 (d, J = 5.5 Hz, 1H), 8.53(s, 1H),8.21 (d, J = 11.1 Hz, 2H), 7.75 (ddd, J = 12.1, 7.8, 2.2 Hz,1H), 7.67-7.48 (m, 2H), 7.38-7.17 (m, 2H), 5.70-5.47 (m, 2H), 3.62(d, J= 11.3 Hz, 1H), 3.14 (d,J = 11.3 Hz, 2H), 3.01 (t, J = 10.1 Hz, 1H),2.68 (s, 3H), 2.35-1.97 (m, 2H), 1.89-1.68 (m, 2H). LC-MS: [M + H]⁺ =579.2, 580.2 167

¹H NMR (400 MHz, CD₃OD) δ ppm 8.42 (s, 1H), 8.18(d, J = 3.0 Hz, 2H),7.51-7.00 (m, 3H), 6.70 (s, 1H), 6.08 (td, J = 55.0, 3.8 Hz, 1H), 5.68(s, 2H), 3.85 (s, 3H), 3.79-3.53 (m, 1H), 3.28-3.03(m, 3H), 2.88 (t, J =11.1 Hz, 1H), 2.07(d, J = 12.0 Hz, 1H), 1.94- 1.59 (m, 3H). LC-MS: [M +H]⁺ = 579.2, 580.2.

Examples 168-176 were prepared from corresponding intermediatesfollowing procedures analogous to the preparation of Example 168 andExample 169.

Example No. Intermediate LC-MS and/or ¹H NMR 168

  or

  168-3 ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.29 (d, J = 13.7 Hz,2H), 7.34 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 7.10 (dd, J =8.6, 2.6 Hz, 1H), 7.02 (s, 1H), 6.92 (d, J = 55.4 Hz, 1H), 6.34-6.01 (m,1H), 5.67 (d, J = 2.2 Hz, 2H), 4.19 (s, 1H), 3.85 (s, 3H), 3.49- 3.37(m, 2H), 3.16-3.02 (m, 2H), 2.02 (d, J = 43.7 Hz, 4H). LC-MS: [M + H]⁺ =545.2, 546.2. 169

¹H NMR (400 MHz, CD₃OD) δ 8.44(s, 1H), 8.20(d, J = 11.9 Hz, 2H), 7.38(d, J = 8.6 Hz, 1H), 6.98-6.87 (m, 3H), 6.08 (td, J = 55.0, 3.9 Hz, 1H),5.69 (s, 2H), 3.80 (s, 3H), 3.69 (d, J = 14.0 Hz, 1H), 3.23 (d, J = 11.5Hz, 1H), 3.18-3.11 (m, 1H), 3.05 (d, J = 11.5 Hz, 1H), 2.88(t, J = 11.0Hz, 1H), 2.03 (dd, J = 24.0, 9.4 Hz, 1H), 1.84 (q, J = 13.7 Hz, 2H),1.72 (d, J = 14.5 Hz, 1H). [M + H]⁺ = 545.2, 546.2. 170

  or

  170-4 ¹H NMR (400 MHz, CD₃OD): δ 8.53(s, 1H), 8.22(s, 1H), 8.21 (s,1H), 7.62-7.57 (m, 1H), 7.39-7.35 (m, 1H), 6.95-6.68 (m, 2H), 6.21-5.93(m, 1H), 5.68 (s, 2H), 3.71 (m, 1H), 3.27-3.24 (m, 2H), 3.10-3.07 1H),2.92-2.87 (m, 1H), 2.05-2.00 (m, 1H), 1.89-1.72 (m, 3H). LC-MS: [M + H]⁺= 567.2. 171

¹H NMR (400 MHz, CD₃OD): δ 8.54 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H),7.61-7.57 (m, 1H), 7.38-7.34 (m, 1H), 6.94-6.66 (m, 2H), 5.68 (s, 2H),4.10-4.01 (m, 1H), 3.27 (m, 1H), 3.07- 3.02 (m, 3H), 1.93-1.71 (m, 4H).LC-MS: [M + H]⁺ = 567.2. 172

  172-4 ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.25 (s, 1H), 8.23 (s,1H), 7.62-7.56 (m, 1H), 7.25- 7.14 (m, 1H), 7.13 (d, J = 1.3 Hz, 1H),6.26-5.92 (m, 1H), 5.70 (s, 2H), 3.79-3.66 (m, 1H), 3.30-3.23 (m, 1H),3.20-3.04 (m, 2H), 2.96-2.85 (m, 1H), 2.15-1.99 (m, 1H), 1.94-1.78 (m,2H), 1.76-1.68 (m, 1H). LC- MS: [M + H]⁺ = 535.4. 173

  or

  173-3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H), 8.26 (s, 1H), 8.14(s, 1H), 7.77 (dd, J = 8.7, 7.2 Hz, 1H), 7.34 (s, 2H), 6.95(s, 1H), 6.89(dd, J = 11.4, 2.5 Hz, 1H), 6.81 (td, J = 8.4, 2.5 Hz, 1H), 6.19 (td, J= 55.8, 4.0 Hz, 1H), 5.74 (s, 1H), 5.54 (d, J = 2.9 Hz, 2H), 3.79 (s,1H), 3.45(s, 3H), 3.17-2.98 (m, 2H), 2.92 (d, J = 8.5 Hz, 1H), 2.75 (d,J = 11.3 Hz, 1H), 2.05-1.62 (m, 5H), 1.47 (d, J = 5.5 Hz, 1H). LC-MS:[M + H]⁺ = 529.0, 530.0. 174

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.43 (s, 1H), 8.26 (s, 1H), 8.14 (s,1H), 7.77 (dd, J = 8.6, 7.2 Hz, 1H), 7.34 (s, 2H), 6.98(s, 1H), 6.89(dd, J = 11.5, 2.5 Hz, 1H), 6.81 (td, J = 8.4, 2.5 Hz, 1H), 6.20 (td, J= 55.4, 3.1 Hz, 1H), 5.64 (d, J = 4.7 Hz, 1H), 5.56 (s, 2H), 3.53 (d, J= 15.7 Hz, 1H), 3.46 (s, 3H), 3.06 (t, J = 11.1 Hz, 2H), 2.95- 2.71 (m,2H), 1.99 (s, 3H), 1.68 (dd, J = 13.1, 8.3 Hz, 2H), 1.53 (d, J = 12.6Hz, 1H). LC-MS: [M + H]⁺ = 529.0, 530.0 175

  or

  175-3 ¹HNMR (400 MHz, CD₃OD) δ 8.50 (s 1H) 8.30-8.24 (m 2H), 8.21 (s,1H), 7.73 (t, J = 8.3 Hz, 1H), 7.69 (s, 1H), 6.21- 5.89 (m, 1H), 5.68(s, 2H), 4.07- 3.90 (m, 1H), 3.29-3.23 (m, 1H), 3.12-2.92 (m, 3H), 2.00-1.88 (m, 3H), 1.72-1.58 (m, 1H) LC-MS: [M + H]⁺ = 534.2. 176

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.33-8.25 (m, 2H), 8.24 (s, 1H),7.82-7.70 (m, 2H), 6.24-5.92 (m, 1H), 5.70 (s, 2H), 3.78-3.64 (m, 1H),3.26 (d, J = 11.5 Hz, 1H), 3.19-3.10 (m, 1H), 3.10- 3.03 (m, 1H),2.95-2.83 (m, 1H), 2.13-1.96(m, 1H), 1.95- 1.77 (m, 2H), 1.76-1.65(m,1H). LC-MS: [M + H]⁺ = 534.4.

Example 177:9-((5-(3-amino-3-(6-methylpyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine

A solution of tert-butyl(tert-butoxycarbonyl)(9-((2-(3,4-difluorophenyl)-5-(3-((methoxycarbonyl)amino)-3-(6-methylpyridin-2-yl)piperidin-1-yl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate(177-7) (700 mg, 0.89 mmol, 10.0 eq) in HBr/AcOH (33%, 10 mL) wasstirred at 25-30° C. for 16 hours. The reaction was concentrated invacuo. The residue was purified by prep-HPLC (0.1% NH₄HCO₃ as additive)to give9-((5-(3-amino-3-(6-methylpyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine(Example 177). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1H), 8.29 (s,1H), 8.14 (s, 1H), 7.93-7.82 (m, 1H), 7.72-7.65 (m, 1H), 7.64-7.59 (m,1H), 7.56 (d, J=7.6 Hz, 1H), 7.52-7.42 (m, 1H), 7.37 (s, 1H), 7.29 (brs,2H), 7.12 (d, J=7.6 Hz, 1H), 5.55 (dd, J=16.0 Hz, 28.4 Hz, 2H), 3.44 (d,J=11.2 Hz, 1H), 3.17-3.08 (m, 1H), 3.06-3.01 (m, 1H), 3.00-2.90 (m, 1H),2.47 (s, 3H), 2.24-2.14 (m, 1H), 2.13-1.99 (m, 1H), 1.77-1.65 (m, 1H).LC-MS: [M+H]⁺=528.3.

Examples 178-284 were prepared following procedures analogous to thepreparation of Example 177 and corresponding intermediates.

Example # Structure ¹H NMR & LC-MS 178

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H),7.74 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.68 (dd, J = 8.3, 7.4 Hz, 1H),7.53 (ddd, J = 10.2, 5.0, 2.9 Hz, 1H), 7.34-7.24 (m, 2H), 7.20 (d, J =7.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.69-5.53 (m, 2H), 3.93 (s, 3H),3.54 (d, J = 11.4 Hz, 1H), 3.23-3.11 (m, 2H), 2.97 (t, J = 10.2 Hz, 1H),2.27 (t, J = 11.2 Hz, 1H), 2.16- 2.01 (m, 1H), 1.97-1.80 (m, 2H). LC-MS:[M + H]⁺ = 544.3, 545.3 179

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.20 (d, J = 14.3 Hz, 2H),7.82 (t, J = 7.8 Hz, 1H), 7.70-7.57 (m, 3H), 7.31 (t, J = 7.9 Hz, 2H),7.24 (s, 1H), 5.74-5.54 (m, 2H), 5.07 (s, 4H), 3.61 (d, J = 11.5 Hz,1H), 3.20-3.10 (m, 2H), 3.01 (t, J = 9.7 Hz, 1H), 2.28 (s, 1H),2.15-1.99 (m, 1H), 1.86 (dq, J = 9.5, 4.8 Hz, 2H). LC-MS: [M + H]⁺ =514.2, 516.1. 180

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.44 (s, 1H), 8.41-8.37 (m,1H), 8.17-8.10 (m, 2H), 7.76 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.42 (s,1H), 7.29 (d, J = 8.0 Hz, 1H), 5.61-5.42 (m, 2H), 4.48 (s, 2H), 3.55 (d,J = 11.1 Hz, 1H), 3.14 (m, 1H), 3.08-2.91 (m, 2H), 2.32-1.75 (m, 4H).LC- MS: [M + H]⁺ = 565.3. 181

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.19 (d, J = 15.0 Hz, 2H),7.82 (t, J = 7.8 Hz, 1H), 7.78-7.59 (m, 2H), 7.32 (d, J = 7.9 Hz, 1H),7.02 (d, J = 1.7 Hz, 1H), 6.80 (dd, J = 8.7, 2.5 Hz, 1H), 6.68 (dd, J =13.3, 2.5 Hz, 1H), 5.65 (t, J = 13.3 Hz, 2H), 3.79 (s, 3H), 3.66-3.54(m, 1H), 3.18 (dt, J = 18.0, 7.7 Hz, 2H), 3.03 (dt, J = 12.4, 6.2 Hz,1H), 2.30 (t, J = 10.0 Hz, 1H), 2.10 (d, J = 12.2 Hz, 1H), 1.88 (q, J =6.8, 5.8 Hz, 2H). LC- MS: [M + H]⁺ = 560.3, 561.3. 182

¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.23 (s 1H) 8.12 (s, 1H),7.78-7.69 (m, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.9, 0.9 Hz,1H), 7.23 (s, 1H), 7.16-7.06 (m, 3H), 5.59 (s, 2H), 3.50 (d, J = 11.3Hz, 1H), 3.13 (dd, J = 15.6, 11.4 Hz, 2H), 3.02-2.84 (m, 1H), 2.31-2.15(m, 1H), 2.15-1.95 (m, 2H), 1.87 (t, J = 7.9 Hz, 2H), 1.07-0.86 (m, 4H).LC-MS: [M + H]⁺ = 536.3, 537.3. 183

¹H NMR (400 MHz, CD₃OD) δ ppm 8.62-8.39 (m, 1H), 8.22 (q, J = 3.4 Hz,1H), 8.19-8.04 (m, 1H), 7.86 (dd, J = 9.7, 5.6 Hz, 1H), 7.74 (qd, J =7.7, 6.5, 3.8 Hz, 2H), 7.62 (q, J = 7.3, 5.7 Hz, 1H), 7.40 (dd, J = 7.5,3.9 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), 7.18-6.96 (m, 2H), 5.80-5.47 (m,3H), 3.68-3.47 (m, 1H), 3.17 (d, J = 11.3 Hz, 2H), 2.97 (d, J = 11.6 Hz,1H), 2.27 (s, 1H), 2.08 (s, 1H), 1.89 (s, 2H), 1.73-1.54 (m, 3H). LC-MS:[M + H]⁺ = 542.3, 543.3 184

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.32-8.06 (m, 3H), 7.97 (d,J = 1.4 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.74-7.58 (m, 3H), 7.43- 7.22(m, 2H), 5.65 (q, J = 16.2 Hz, 2H), 3.90 (s, 3H), 3.61 (d, J = 11.3 Hz,1H), 3.14 (d, J = 11.5 Hz, 2H), 3.06-2.88 (m, 1H), 2.28 (t, J = 10.6 Hz,1H), 2.05 (dq, J = 13.6, 5.3, 4.2 Hz, 1H), 1.92- 1.78 (m, 2H). LC-MS:[M + H]⁺ = 566.3, 568.3. 185

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.20 (d, J = 25.6 Hz, 2H),7.81 (t, J = 7.8 Hz, 1H), 7.72-7.55 (m, 2H), 7.43 (dd, J = 8.4, 2.0 Hz,1H), 7.31 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 6.72 (d, J = 8.3 Hz, 1H),5.61 (q, J = 16.3 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.58(d, J = 11.3Hz, 1H), 3.19 (t, J = 8.7 Hz, 2H), 3.11 (d, J = 11.3 Hz, 2H), 3.03- 2.92(m, 1H), 2.26 (d, J = 9.2 Hz, 1H), 2.11- 1.99 (m, 1H), 1.92-1.77 (m,2H). LC-MS: [M + H]⁺ = 554.3, 555.2. 186

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.20 (d, J = 21.9 Hz, 2H),7.81 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.8 Hz,1H), 7.24 (d, J = 1.8 Hz, 1H), 7.20-7.12 (m, 2H), 6.82 (d, J = 8.1 Hz,1H), 5.96 (s, 2H), 5.61 (q, J = 16.3 Hz, 2H), 3.58 (d, J = 11.3 Hz, 1H),3.18-3.03 (m, 2H), 3.03-2.94 (m, 1H), 2.27 (s, 1H), 2.04 (dt, J = 11.1,5.6 Hz, 1H), 1.84 (td, J = 12.2,11.2, 4.7 Hz, 2H). LC-MS: [M + H]⁺ =556.3, 557.2. 187

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H),7.87-7.78 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (m, 1H), 7.32 (d, J =8.0 Hz, 1H), 7.09 (s, 1H), 6.89 (m, 1H), 5.72- 5.55 (m, 2H), 3.86 (s,3H), 3.69-3.54 (m, 1H), 3.25-3.12 (m, 2H), 3.10-2.97 (m, 1H), 2.36- 2.23(m, 1H), 2.19-2.04 (m, 1H), 1.88 (m, 2H). LC-MS: [M + H]⁺ = 578.4. 188

¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.21 (d, J = 15.8 Hz, 2H),7.70 (d, J = 5.7 Hz, 2H), 7.54 (dd, J = 12.7, 2.2 Hz, 1H), 7.44 (dt, J =8.6, 1.5 Hz, 1H), 7.22 (s, 1H), 7.08 (t, J = 8.6 Hz, 1H), 5.82-5.45 (m,2H), 3.86 (s, 3H), 3.54 (d, J = 11.4 Hz, 1H), 3.11 (dd, J = 17.2, 8.3Hz, 2H), 3.02- 2.89 (m, 1H), 2.33-2.16 (m, 1H), 2.12-1.94 (m, 1H),1.92-1.71 (m, 2H). LC-MS: [M + H]⁺ = 578.3, 579.3 189

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H),8.21 (s, 1H), 7.79-7.76 (m, 3H), 7.64-7.60 (m, 1H), 7.28 (s, 1H), 7.14(t, J = 8.8 Hz, 1H), 5.70-5.61 (m, 2H), 3.56 (d, J = 11.0 Hz, 1H),3.23-3.15 (m, 2H), 3.00 (t, J = 10 Hz, 1H), 2.33-2.21 (m, 1H), 2.16-2.05(m, 1H), 1.95-1.85 (m, 2H). LC-MS: [M + H]⁺ = 514.3. 190

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H),7.84-7.68 (m, 2H), 7.57-7.41 (m, 2H), 7.25 (s, 1H), 7.16-7.04 (m, 2H),5.73-5.47 (m, 2H), 3.53 (d, J = 11.4 Hz, 1H), 3.15 (d, J = 11.3 Hz, 2H),2.97 (td, J = 11.2, 10.5, 2.9 Hz, 1H), 2.48 (d, J = 3.0 Hz, 3H), 2.36-2.19 (m, 1H), 2.06 (dtt, J = 13.8, 8.3, 4.4 Hz, 1H), 1.95-1.76 (m, 2H).LC-MS: [M + H]⁺ = 527.8, 528.8. 191

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.29-8.24 (m, 1H), 8.24-8.19(m, 2H), 7.85- 7.79 (m, 1H), 7.77-7.70 (m, 2H), 7.66 (d, J = 7.7 Hz,1H), 7.33 (d, J = 7.7 Hz, 1H), 5.73-5.56 (m, 2H), 3.69-3.59 (m, 1H),3.27-3.16(m, 2H), 3.10- 2.98 (m, 1H), 2.38-2.24 (m, 1H), 2.19-2.02 (m,1H), 1.94-1.81 (m, 2H). LC-MS: [M + H]⁺ = 192

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.19 (d, J = 18.0 Hz, 2H),7.74 (dd, J = 11.9, 8.1 Hz, 1H), 7.62 (t, J = 9.8 Hz, 1H), 7.57-7.49 (m,1H), 7.44-7.35 (m, 1H), 7.29 (d, J = 16.6 Hz, 2H), 5.61 (s, 2H), 3.73(d, J = 11.5 Hz, 1H), 3.25 (d, J = 11.6 Hz, 1H), 3.14 (d, J = 11.7 Hz,1H), 2.99 (t, J = 10.5 Hz, 1H), 2.31 (d, J = 12.5 Hz, 1H), 2.11 (d, J =10.7 Hz, 1H), 1.99 (d, J = 13.1 Hz, 1H), 1.87 (d, J = 12.5 Hz, 1H).LC-MS: [M + H]⁺ = 566.2, 567.2. 193

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H),7.83-7.71 (m, 3H), 7.70-7.61 (m, 1H), 7.23 (s, 1H), 7.13 (t, J = 8.8 Hz,2H), 5.72-5.40 (m, 4H), 3.67-3.54 (m, 1H), 3.22-3.09 (m, 2H), 3.00 (t, J= 8.8 Hz, 1H), 2.39- 2.23 (m, 1H), 2.13-2.02 (m, 1H), 1.94-1.79 (m, 2H).LC-MS: [M + H]⁺ = 546.1. 194

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.25-8.21 (m, 2H), 8.18-8.13(d, J = 8.8 Hz, 1H), 7.85-7.78 (t, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.68-7.63 (d, J = 8.0 Hz, 1H), 7.54-7.48 (d, J = 8.0 Hz, 1H), 7.34-7.31 (d, J= 8.0 Hz, 1H), 5.71-5.59 (m, 2H), 3.94 (s, 3H), 3.67-3.57 (m, 1H),3.22-7.15 (m, 2H), 3.09-2.99 (m, 1H), 2.35-2.25 (m, 1H), 2.15-2.04 (m,1H), 1.94-1.83 (m, 2H). LC-MS: [M + H]⁺ = 577.3. 195

¹H NMR (400 MHz, CD₃OD): δ 8.59 (s, 1H), 8.25- 8.20 (m, 2H), 8.05-8.01(m, 2H), 7.91 (d, J = 6.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.57-7.54 (m, 1H),7.32-7.27 (m, 2H), 5.70-5.56 (m, 2H), 3.68 (d, J = 11.6 Hz, 1H),3.28-3.05 (m, 3H), 2.40-2.31 (m, 1H), 2.12-1.90 (m, 3H). LC-MS: [M + H]⁺= 557.1 196

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1H), 8.40 (d, J = 2.3 Hz, 1H),8.31 (dd, J = 4.6, 9.0 Hz, 1H), 8.23 (d, J = 5.5 Hz, 2H), 7.89-7.82 (m,1H), 7.76 (s, 1H), 7.72-7.60 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H),5.76-5.59 (m, 2H), 3.66 (d, J = 11.0 Hz, 1H), 3.29-3.19 (m, 2H),3.12-3.03 (m, 1H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 1H), 1.93-1.90 (m).LC-MS: [M + H]⁺ = 531.3. 197

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H),7.95 (t, J = 7.9 Hz, 1H), 7.84-7.67 (m, 3H), 7.59 (dd, J = 7.8, 0.9 Hz,1H), 7.22 (s, 1H), 7.18-7.02 (m, 2H), 5.79-5.43 (m, 2H), 3.60 (d, J =11.3 Hz, 1H), 3.24-3.09 (m, 2H), 3.04-2.90 (m, 1H), 2.35-2.24 (m, 1H),2.11 (t, J = 5.0 Hz, 1H), 2.01 (t, J = 18.7 Hz, 3H), 1.94-1.82 (m, 2H).LC-MS: [M + H]⁺ = 560.3, 561.3. 198

¹H NMR (400 MHz, DMSO-d₆ ) δ ppm 8.50-8.56 (2H, m), 8.28 (1H, s), 8.13(1H, s), 7.85-7.95 (1H, m), 7.78 (2H, d, J = 3.6 Hz), 7.55-7.65 (1H, m),7.40-7.50 (1H, m), 7.36 (1H, s), 7.20-7.35 (3H, m), 5.55 (2H, dd, J =23.2, 16.4 Hz), 3.45 (1H, d, J = 11.2 Hz), 3.15-3.07 (1H, m), 3.04 (1H,d, J = 11.2 Hz), 2.93 (1H, t, J = 10.8 Hz), 2.00-2.25 (2H, m), 1.60-1.80(2H, m), 1.10-1.30 (2H, m). LC-MS: [M + H]⁺ = 514.2. 199

¹H NMR (400 MHz, DMSO-d₆ ) δ ppm 8.57 (s, 1H), 8.41-8.38 (m, 1H), 8.23(s, 1H), 8.12 (s, 1H), 7.93-7.85 (m, 1H), 7.72-7.60 (m, 2H), 7.53-7.45(m, 1H), 7.43-7.38 (m, 1H), 7.37 (s, 1H), 7.28 (s, 2H), 5.55-5.44 (m,2H), 3.57(d, J = 11.6 Hz, 1H), 3.25 (d, J = 11.6 Hz, 1H), 3.13-3.05 (m,1H), 2.94 (t, J = 8.8 Hz, 1H), 2.20-2.07 (m, 2H), 1.94 (brs, 1H),1.81-1.74 (m, 1H). LC-MS: [M + H]⁺ = 532.1. 200

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H),7.83 (t, J = 7.6 Hz, 1H), 7.77-7.72 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H),7.57- 7.50 (m, 1H), 7.35-7.24 (m, 3H), 5.67 (d, J = 16.0 Hz, 1H), 5.60(d, J = 16.0 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.19-3.11 (m, 2H), 3.01(t, J = 9.2 Hz, 1H), 2.34-2.24 (m, 1H), 2.14-2.02 (m, 1H), 1.94-1.82 (m,2H). LC-MS: [M + H]⁺ = 548.3. 201

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.22 (d, J = 19.8 Hz, 2H),7.96 (q, J = 8.1 Hz, 1H), 7.75 (ddd, J = 12.1, 7.8, 2.3 Hz, 1H),7.64-7.49 (m, 2H), 7.41-7.19 (m, 2H), 6.95 (dd, J = 8.1, 2.9 Hz, 1H),5.86-5.56 (m, 2H), 3.57 (d, J = 11.3 Hz, 1H), 3.16 (dd, J = 14.3, 10.2Hz, 2H), 3.06- 2.93 (m, 1H), 2.27 (dq, J = 14.8, 6.5, 5.3 Hz, 1H), 2.09(tdd, J = 13.4, 8.4, 4.1 Hz, 1H), 1.95-1.68 (m, 2H). LC-MS: [M + H]⁺ =532.0, 533.0. 202

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (d, J = Hz, 1H), 8.22 (d, J = 34.2Hz, 2H), 7.78 (ddd, J = 13.6, 7.9, 5.0 Hz, 3H), 7.50 (d, J = 7.9 Hz,1H), 7.31 (s, 1H), 7.16 (td, J = 9.6, 8.7, 4.3 Hz, 3H), 5.63 (t, J =10.3 Hz, 2H), 3.59 (d, J = 11.6 Hz, 1H), 3.24-3.15 (m, 2H), 3.03 (dt, J= 11.3, 5.9 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 2.32 (t, J = 11.3 Hz,1H), 2.17-2.02 (m, 1H), 2.01-1.82(m, 2H), 1.30 (q, J = 6.2, 4.7 Hz, 3H).LC-MS: [M + H]⁺ = 524.0, 525.0. 203

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.30-8.20 (m, 1H), 8.17 (d,J = 7.5 Hz, 1H), 8.00 (q, J = 7.2, 6.5 Hz, 1H), 7.86 (d, J = 8.0 Hz,1H), 7.77 (ddd, J = 9.2, 5.7, 2.9 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H),7.23 (d, J = 7.5 Hz, 1H), 7.14 (td, J = 8.9, 4.5 Hz, 2H), 6.72 (td, J =55.4, 7.7 Hz, 1H), 5.77-5.49 (m, 2H), 3.65 (d, J = 11.4 Hz, 1H), 3.19(t, J = 9.9 Hz, 2H), 3.09-2.91 (m, 1H), 2.33 (q, J = 9.5, 6.1 Hz, 1H),2.12 (dp, J = 14.5, 4.3 Hz, 1H), 1.99-1.80 (m, 2H). LC-MS: [M + H]⁺ =546.0, 547.0. 204

¹H NMR (CD₃OD) δ: 8.24 (d, J = 18.9 Hz, 2H), 8.12 (s, 1H), 7.80 (t, J =7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.61(s, 1H), 5.54 (q, J = 16.5 Hz, 2H), 3.51 (d, J = 11.4 Hz, 1H), 3.04 (d,J = 11.2 Hz, 2H), 2.92 (t, J = 10.5 Hz, 1H), 2.25 (s, 1H), 2.00 (d, J =10.4 Hz, 1H), 1.93-1.72 (m, 3H), 0.89 (dt, J = 8.3, 3.2 Hz, 2H),0.84-0.67 (m, 2H) LC-MS [M + H]⁺ = 476.3 205

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H),7.81 (t, J = 8.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.11 (t, J = 8.8 Hz, 2H),5.69-5.58 (m, 2H), 3.59 (d, J = 11.2 Hz, 1H), 3.14 (d, J = 11.2 Hz, 1H),2.98 (t, J = 9.6 Hz, 1H), 2.30-2.25 (m, 1H), 2.13-2.00 (m, 1H), 1.90-1.76 (m, 2H). LC-MS: [M + H]⁺ = 530.1. 206

¹H NMR (400 MHz, CD₃OD): □ 8.57 (s, 1H), 8.26 d, J = 3.2 Hz, 2H),7.83-7.73 (m, 1H), 7.67-7.52 (m, 1H), 7.45 (s, 1H), 7.35-7.21 (m, 1H),6.67 (s, 1H), 6.00 (s, 1H), 5.68-5.56 (m, 2H), 3.54-3.44 (m, 1H),3.14-2.97 (m, 2H), 2.28-2.15 (m, 1H), 2.10-1.95 (m, 2H), 1.89-1.85 (m,2H). LC-MS: [M + H]⁺ = 548.3. 207

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.23(d, J = 6.2 Hz, 1H),8.18(s, 1H), 7.59-7.40 (m, 4H), 7.23 (s, 1H), 7.06 (t, J = 8.6 Hz, 1H),5.68- 5.49 (m, 2H), 3.86 (s, 3H), 3.49 (d, J = 11.3 Hz, 1H), 3.11 (dd, J= 11.6, 5.1 Hz, 2H), 2.92 (td, J = 15.9, 14.2, 8.1 Hz, 1H), 2.47 (d, J =2.9 Hz, 3H), 2.21 (q, J = 8.5, 5.8 Hz, 1H), 2.04 (qd, J = 10.4, 9.8, 5.0Hz, 1H), 1.92-1.74 (m, 2H). LC-MS: [M + H]⁺ = 558.4. 208

¹H NMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1H), 8.23 (d, J = 9.6 Hz, 2H),8.03 (d, J = 3.6 Hz, 2H), 7.77-7.72 (m, 2H), 7.53 (s, 1H), 7.30-7.25 (m,2H), 5.69-5.59 (m, 2H), 3.66 (d, J = 11.2 Hz, 1H), 3.21-3.13 (m, 2H),3.03 (t, J = 10.0 Hz, 1H), 2.35- 2.29 (m, 1H), 2.18-2.05 (m, 1H),1.91-1.83 (m, 2H). LC-MS: 561.1 [M + Na]⁺. 209

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H),8.22 (d, J = 9.8 Hz, 2H), 7.84-7.71 (m, 2H), 7.65 (dd, J = 8.7, 2.8 Hz,1H), 7.54 (ddd, J = 8.0, 4.0, 1.9 Hz, 1H), 7.39- 7.19 (m, 2H), 6.92 (t,J = 73.1 Hz, 1H), 5.63 (s, 2H), 3.56 (d, J = 11.4 Hz, 1H), 3.18 (dd, J =25.0, 11.9 Hz, 2H), 3.06-2.92 (m, 1H), 2.25 (q, J = 13.9, 12.5 Hz, 1H),2.08 (q, J = 12.2 Hz, 1H), 2.01- 1.82 (m, 2H). LC-MS: [M + H]⁺ = 580.3,581.3. 210

¹H NMR (400 MHz, CD₃OD) δ ppm 8.90 (d, J = 1.5 Hz, 1H), 8.54 (s, 1H),8.21 (d, J = 15.3 Hz, 2H), 7.94-7.76 (m, 2H), 7.75-7.60 (m, 2H),7.59-7.49 (m, 2H), 7.36 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 5.84-5.50 (m,2H), 3.60 (d, J = 11.3 Hz, 1H), 3.14 (dd, J = 11.4, 4.5 Hz, 2H), 3.02-2.90 (m, 1H), 2.26 (q, J = 9.5, 6.1 Hz, 1H), 2.06 (tp, J = 7.9, 4.4, 3.7Hz, 1H), 1.84 (q, J = 7.8, 4.3 Hz, 2H). LC-MS: [M + H]⁺ = 552.3, 553.2.211

¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.21 (d, J = 20.6 Hz, 2H),7.82 (t, J = 7.8 Hz, 1H), 7.71-7.56 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H),7.17 (s, 1H), 7.01-6.83 (m, 2H), 5.62 (q, J = 16.4 Hz, 2H), 3.80 (s,3H), 3.59 (d, J = 11.3 Hz, 1H), 3.12 (d, J = 11.4 Hz, 2H), 2.99 (t, J =10.4 Hz, 1H), 2.27 (s, 1H), 2.04 (d, J = 9.8 Hz, 1H), 1.92-1.75 (m, 2H).LC-MS: [M + H]⁺ = 542.3, 544.3. 212

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (d, J = 4.2 Hz, 1H), 8.29-8.18 (m,1H), 8.13 (s, 1H), 7.86 (dd, J = 10.1, 6.1 Hz, 1H), 7.75 (dd, J = 8.8,5.0 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.22(d, J = 5.9 Hz, 1H), 7.18-7.00 (m, 2H), 5.79-5.50 (m, 3H), 3.57 (d, J =11.3 Hz, 1H), 3.16 (d, J = 10.8 Hz, 2H), 3.01 (d, J = 13.3 Hz, 1H), 2.29(s, 1H), 2.07 (s, 1H), 1.89 (d, J = 11.2 Hz, 2H), 1.77-1.55 (m, 3H).LC-MS: [M + H]⁺ = 542.3, 543.3. 213

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H),7.81 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.54 (dd, J = 12.7,2.2 Hz, 1H), 7.44 (ddd, J = 8.6, 2.2, 1.1 Hz, 1H), 7.31 (d, J = 7.8 Hz,1H), 7.21 (s, 1H), 7.08 (t, J = 8.7 Hz, 1H), 5.61 (q, J = 16.3 Hz, 2H),3.87 (s, 3H), 3.66-3.50 (m, 1H), 3.12 (d, J = 11.4 Hz, 2H), 2.96 (d, J =9.6 Hz, 1H), 2.25 (d, J = 10.5 Hz, 1H), 2.04 (ddt, J = 13.6, 9.6, 4.8Hz, 1H), 1.88-1.68 (m, 2H). LC-MS: [M + H]⁺ = 560.3, 561.2. 214

¹H NMR (400 MHz, CD₃OD) δ ppm 8.60 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H),7.81 (ddd, J = 2.0, 7.9, 11.8 Hz, 1H), 7.62 (br d, J = 8.4 Hz, 1H), 7.52(s, 1H), 7.46-7.39 (m, 2H), 7.37-7.26 (m, 1H), 5.65 (m, 2H), 3.59-3.52(m, 1H), 3.48-3.41 (m, 1H), 3.13-3.01 (m, 2H), 2.38-2.17 (m, 2H), 2.09-1.91 (m, 2H).LC-MS: [M + H]⁺ = 548.0. 215

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1H), 8.26 (s, 1H), 8.19 (s, 1H),8.12-8.02 (m, 1H), 7.83-7.73 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.59-7.50(m, 1H), 7.36-7.25 (m, 2H), 5.74-5.59 (m, 2H), 5.10-5.00 (m, 1H),3.65-3.53 (m, 1H), 3.23- 3.12 (m, 2H), 3.10-2.95 (m, 1H), 2.37-2.22 (m,1H), 2.14-2.00 (m, 1H), 1.94-1.81 (m, 2H), 1.45 (d, J = 6.8 Hz, 1H),1.41 (d, J = 6.4 Hz, 2H). LC-MS: [M + H]⁺ = 576.3. 216

¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1H), 8.21 (d, J = 16.6 Hz, 2H),7.71 (d, J = 5.8 Hz, 2H), 7.68-7.56 (m, 2H), 7.17 (s, 1H), 7.03-6.81 (m,2H), 5.71-5.49 (m, 2H), 3.55 (d, J = 11.4 Hz, 1H), 3.11 (td, J = 9.8,8.6, 4.4 Hz, 2H), 3.04-2.91 (m, 1H), 2.26 (t, J = 10.9 Hz, 1H), 2.04(dq, J = 13.1, 8.6, 7.5 Hz, 1H), 1.91-1.74 (m, 2H). LC- MS: [M + H]⁺ =560.3, 561.3 217

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.29 (s, 1H), 8.23 (s, 1H),7.75 (ddd, J = 11.8,7.9, 2.1 Hz, 1H), 7.67 (dd, J = 8.9, 7.2 Hz, 1H),7.54 (d, J = 8.8 Hz, 1H), 7.30 (dt, J = 16.6, 5.6 Hz, 2H), 6.78 (s, 1H),6.51 (d, J = 8.9 Hz, 1H), 5.76-5.60 (m, 2H), 3.39 (d, J = 11.6 Hz, 1H),3.21 (d, J = 11.3 Hz, 1H), 3.14 (d, J = 12.1 Hz, 1H), 3.01 (t, J = 10.8Hz, 1H), 2.16 (d, J = 10.1 Hz, 2H), 1.89(d, J = 17.2 Hz, 2H). LC-MS:[M + H]⁺ = 530.3, 531.3. 218

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H),7.92 (dd, J = 9.0, 3.6 Hz, 1H), 7.80-7.68 (m, 3H), 7.22 (s, 1H), 7.12(t, J = 8.8 Hz, 2H), 6.87 (t, J = 53.6 Hz, 1H), 5.71- 5.51 (m, 2H),3.60(d, J = 11.3 Hz, 1H), 3.15(d, J = 17.2 Hz, 2H), 3.00 (t, J = 10.7Hz, 1H), 2.30 (t, J = 11.7 Hz, 1H), 2.08 (d, J = 12.7 Hz, 1H), 1.94-1.79(m, 2H). LC-MS: [M + H]⁺ = 563.9. 219

¹H NMR (400 MHz, CD₃OD) δ ppm 7.83-7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.51(s, 1H), 7.34-7.27 (m, 1H), 6.72-6.71 (d, J = 1.6 Hz, 1H), 6.49-6.48 (d,J = 1.6 Hz, 1H), 5.67-5.59 (t, Ji = 16.4 Hz, ../2 = 33.6 Hz, 2H),3.55-3.52 (d, J = 12.0 Hz, 1H), 3.35 (s, 1H), 3.08-3.06 (m, 2H),2.28-2.22 (m, 1H), 2.13-2.09 (m, 1H), 2.00-1.91 (m, 2H). LC-MS: [M + H]⁺= 564.3 220

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.32-8.06 (m, 3H), 7.97 (d,J = 1.4 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.74-7.58 (m, 3H), 7.43- 7.22(m, 2H), 5.65 (q, J = 16.2 Hz, 2H), 3.90 (s, 3H), 3.61 (d, J = 11.3 Hz,1H), 3.14 (d, J = 11.5 Hz, 2H), 3.06-2.88 (m, 1H), 2.28 (t, J = 10.6 Hz,1H), 2.05 (dq, J = 13.6, 5.3, 4.2 Hz, 1H), 1.92- 1.78 (m, 2H). LC-MS:[M + H]⁺ = 566.3, 568.3. 221

¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H), 8.21 (d, J = 11.4 Hz, 2H),7.80-7.66 (m, 4H), 7.23 (s, 1H), 7.18-7.08 (m, 2H), 5.71-5.52 (m, 2H),3.57 (d, J = 11.4 Hz, 1H), 3.14 (t, J = 11.0 Hz, 2H), 2.99 (td, J =10.7, 9.6, 2.8 Hz, 1H), 2.25 (d, J = 9.7 Hz, 1H), 2.12-1.97 (m, 1H),1.91-1.77 (m, 2H). LC-MS: [M + H]⁺ = 547.7. 222

¹H NMR (400 MHz, CD₃OD) δ ppm 8.99 (t, J = 4.9 Hz, 1H), 8.58 (q, J = 4.7Hz, 1H), 8.22 (dq, J = 16.5, 4.4 Hz, 2H), 8.01-7.91 (m, 1H), 7.81 (dd, J= 11.4, 6.7 Hz, 1H), 7.65 (dh, J = 14.1, 7.6, 6.2 Hz, 3H), 7.44-7.24 (m,2H), 6.61 (d, J = 6.6 Hz, 1H), 5.66 (d, J = 9.9 Hz, 2H), 3.62 (s, 1H),3.15 (q, J = 7.6, 6.8 Hz, 2H), 3.02 (d, J = 9.4 Hz, 1H), 2.36-2.15 (m,2H), 2.07 (s, 1H), 1.87 (s, 2H). LC-MS: [M + H]⁺ = 552.3, 554.3. 223

¹H NMR (400 MHz, CD₃OD) δ ppm 8.60 (s, 1H), 8.20 (d, J = 7.6 Hz, 2H),7.90-7.77 (m, 2H), 7.76 (d, J = 5.5 Hz, 2H), 7.65 (dd, J = 7.8, 0.7 Hz,1H), 7.43 (s, 1H), 7.37-7.27 (m, 1H), 5.79-5.42 (m, 2H), 3.64 (d, J =11.3 Hz, 1H), 3.18 (dd, J = 11.6, 6.3 Hz, 2H), 3.09-2.91 (m, 1H),2.36-2.20 (m, 1H), 2.20-2.03 (m, 1H), 1.87 (dd, J = 11.3, 6.1 41, F Hz,2H). LC-MS: [M + H]⁺ = 555.3, 557.2. 224

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.23-8.20 (m, 2H), 8.10-8.06(d, J = 8.0 Hz, 1H), 7.85-7.79 (t, J = 8.0 Hz, 1H), 7.68-7.65 (d, J =8.0 Hz, 1H), 7.62-7.55 (m, 2H), 7.34-7.31 (d, J = 8.0 Hz, 1H), 5.67-5.61(m, 2H), 3.92 (s, 3H), 3.65- 3.58 (m, 1H), 3.52-3.45 (m, 1H), 3.25-2.98(m, 2H), 2.38-2.23 (m, 1H), 2.20-2.03(m, 1H),1.94 - 1.82 (m, 2H). LC-MS:[M + H]⁺ = 561.3. 225

¹H NMR (CD₃OD) δ: 8.51 (s, 1H), 8.22 (d, J = 13.4 Hz, 2H), 8.05 (dd, J =27.2, 1.0 Hz, 2H), 7.93 - 7.74 (m, 2H), 7.60 (dd, J = 39.0, 8.3 Hz, 2H),7.43-7.19 (m, 2H), 5.64 (q, J = 16.4 Hz, 2H), 4.04 (s, 3H), 3.59 (d, J =11.4 Hz, 1H), 3.13 (d, J = 11.4 Hz, 2H), 3.07-2.83 (m, 1H), 2.32-1.99(m, 2H), 1.84 (td, J = 11.9, 10.8, 4.6 Hz, 2H) LC- MS : [M + H]⁺ = 566.3: [M + H]⁺ = 568.3. 226

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H),7.88 (t, J = 7.8 Hz, 1H), 7.74 (ddd, J = 12.1, 7.8, 2.3 Hz, 1H), 7.65(d, J = 8.0 Hz, 1H), 7.53 (ddt, J = 8.2, 4.0, 1.6 Hz, 1H), 7.40 (d, J =7.7 Hz, 1H), 7.33-7.22 (m, 2H), 5.68- 5.52 (m, 2H), 5.51 (s, 1H), 5.39(s, 1H), 3.59 (d, J = 11.6 Hz, 1H), 3.16 (dd, J = 11.7, 6.2 Hz, 2H),3.00(t, J = 10.0 Hz, 1H), 2.30(t, J = 11.0 Hz, 1H), 2.08 (d, J = 9.5 Hz,1H), 1.97-1.80 (m, 2H). LC- MS: [M + H]⁺ = 545.9, 546.9. 227

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H),7.99 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 (ddd, J = 11.8,7.8, 2.1 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.56-7.43 (m, 1H), 7.27 (d,J = 9.6 Hz, 2H), 6.71 (t, J = 55.4 Hz, 1H), 5.72-5.50 (m, 2H), 3.63 (d,J = 11.4 Hz, 1H), 3.17(t, J = 11.6 Hz, 2H), 3.09-2.94 (m, 1H),2.31 (t, J= 11.5 Hz, 1H), 2.16-1.98 (m, 1H), 1.95-1.79 (m, 2H). LC-MS: [M + H]⁺ =564.3, 565.3. 228

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.20 (d, J = 16.4 Hz, 2H),7.81 (t, J = 7.8 Hz, 1H), 7.77-7.68 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H),7.54 (d, J = 8.6 Hz, 1H), 7.40-7.24 (m, 3H), 6.87 (t, J = 73.3 Hz, 1H),5.72-5.49 (m, 2H), 3.61 (d, J = 11.4 Hz, 1H), 3.14 (d, J = 11.1 Hz, 2H),3.00 (t, J = 10.5 Hz, 1H), 2.35-2.17 (m, 1H), 2.06 (d, J = 10.1 Hz, 1H),1.86 (q, J = 11.0, 8.6 Hz, 2H). LC- MS: [M + H]⁺ = 596.3, 597.2. 229

¹H NMR (400 MHz, CD₃OD) δ ppm 8.79 (d, J = 2.3 Hz, 1H), 8.57 (s, 1H),8.21 (d, J = 13.1 Hz, 2H), 8.08 (dd, J = 8.2, 2.4 Hz, 1H), 7.82 (t, J =7.8 Hz, 1H), 7.65 (dd, J = 7.8, 0.7 Hz, 1H), 7.40- 7.20 (m, 3H),5.72-5.54 (m, 2H), 3.62 (d, J = 11.4 Hz, 1H), 3.15(d, J = 11.0 Hz, 2H),3.02 (t, J = 10.5 Hz, 1H), 2.29 (s, 1H), 2.08 (d, J = 12.8 Hz, 1H), 1.87(d, J = 7.5 Hz, 2H). LC-MS: [M + H]⁺ = 527.3, 528.3. 230

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H),7.75-7.70 (m, 1H), 7.53-7.48 (m, 2H), 7.31-7.23 (m, 3H), 5.63-5.53 (q,2H), 3.95 (s, 3H), 3.76-3.73 (m, 1H), 3.27 (s, 1H), 3.17-3.14 (m, 1H),3.00-2.95 (m, 1H), 2.30- 2.27 (m, 1H), 2.09-1.96 (m, 3H). LC-MS: [M +H]⁺ = 578.4. 231

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H),8.24 (s, 1H), 8.22 (s, 1H), 7.93 (dd, J = 1.9, 11.4 Hz, 1H), 7.88 (br t,J = 7.9 Hz, 1H), 7.70 (br d, J = 7.7 Hz, 1H), 7.39 (br d, J = 7.9 Hz,1H), 7.35 (s, 1H), 5.80-5.49 (m, 2H), 4.01 (s, 3H), 3.58 (br d, J = 10.3Hz, 1H), 3.20 (br d, J = 10.5 Hz, 1H), 3.12 (br d, J = 10.3 Hz, 1H),3.06-2.96 (m, 1H), 2.39-2.24 (m, 1H), 2.14- 1.80 (m, 4H). LCMS: [M + H]⁺= 561.4 232

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.20 (s, 2H), 7.82-7.58 (m,2H), 7.53-7.39 (m, 3H), 7.26 (dt, J = 10.4, 8.4 Hz, 1H), 7.19 (s, 1H),5.84-5.33 (m, 2H), 3.87-3.39 (m, 2H), 3.13 (t, J = 5.3 Hz, 2H), 2.47 (s,4H), 2.25-1.77 (m, 3H). LC-MS: [M + H]⁺ = 544.2, 545.3 233

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.29-8.21 (m, 1H), 8.17 (s,1H), 7.81 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.47-7.36 (m,2H), 7.35-7.27 (m, 2H), 5.68-5.52 (m, 2H), 3.96 (s, 3H), 3.63-3.54 (m,1H), 3.18-3.06 (m, 2H), 3.02-2.92 (m, 1H), 2.33-2.19 (m, 1H), 2.12- 1.98(m, 1H), 1.92-1.79 (m, 2H). LC-MS: [M + H]⁺ = 578.0. 234

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H),8.07 (d, J = 8.2 Hz, 1H), 7.80-7.71 (m, 2H), 7.55 (br s, 1H), 7.35-7.27(m, 2H), 5.66-5.57 (m, 2H), 5.11 (m, 1H), 3.66 (m, 1H), 3.22-3.14 (m,2H), 3.05 (m, 1H), 2.34 (m, 1H), 2.08 (m, 1H), 1.91 (m, 2H), 1.35 (m,3H). LC-MS: [M + H]⁺ = 592.4 235

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.23(s, 1H), 8.18 (s, 1H),7.73 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.58 7.44 (m, 1H), 7.32 (s, 1H),F 7.27 (dt, J = 10.3, 8.4 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.49 (d, J= 1.8 Hz, 1H), 5.72-5.54 (m, 2H), 3.91 (s, 3H), 3.51 (d, J = 11.4 Hz,1H), 3.11 (d, J = 10.8 Hz, 2H), 2.96 (t, J = 10.7 Hz, 1H), 2.21 (t, J =10.8 Hz, 1H), 2.13-1.95 (m, 1H), 1.89-1.73 (m, 2H). LC-MS: [M + H]⁺ =562.0, 563.0. 236

₁H NMR (400 MHz, CD₃OD): ): δ 8.55 (s, 1H), 8.22 (s, 1H), 8.18(s, 1H),7.86-7.82 (t, J = 8.0 Hz, 1H), 7.69-7.68 (d, J = 7.6 Hz, 1H), 7.35-7.34(d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.63-6.60 (m, 2H), 5.72-5.62 (m, 2H),3.82 (s, 3H), 3.69-3.61 (m, 1H), 3.27-3.20 (m, 2H), 3.10-3.05 (m, 1H),2.35- 2.31 (m, 1H), 2.16-2.14 (m, 1H), 1.92-1.90 (m, 2H). LCMS: [M + H]⁺= 578.3. 237

¹H NMR (400 MHz, CD₃OD) δ ppm 8.57 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H),7.85-7.81 (t, J = 8.0 Hz, 1H), 7.79-7.74 (m, 1H), 7.68-7.66 (d, J = 7.6Hz, 1H), 7.34-7.32 (d, J = 8.0 Hz, 1H), 7.20-7.15 (m, 1H), 7.13(br, 1H),5.69-5.60 (m, 2H), 3.65-3.62 (d, J = 11.2 Hz,1H), 3.24-3.18 (m, 2H),3.08-3.03 (m, 1H), 2.34-2.27 (m,1H), 2.17-2.11 (m, 1H), 1.91-1.88 (m,2H). LC-MS: [M + H]⁺ = 566.4. 238

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H),7.85-7.76 (m, 2H), 7.68-7.66 (d, J = 8.0 Hz, 1H), 7.34-7.32 (d, J = 7.6Hz, 1H), 7.07-6.94 (m, 3H), 5.70-5.60 (m, 2H), 3.65-3.62 (d, J = 11.2Hz,1H), 3.23-3.13 (m, 2H), 3.07-3.02 (m, 1H), 2.31-2.28 (m,1H),2.13-2.11 (m, 1H), 1.90-1.88 (m, 2H). LC-MS: [M + H]⁺ = 548.4. 239

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H),7.74 (m, 1H), 7.58- 7.51 (m, 1H), 7.34 (s, 1H), 7.27 (q, J = 8.4 Hz,1H), 7.17 (dd, J = 6.8, 8.8 Hz, 1H), 6.77 (dd, J = 3.6, 8.4 Hz, 1H),5.75-5.62 (m, 2H), 3.39-3.33 (m, 2H), 3.20-3.13 (m, 1H), 2.90 (dt, J =2.8, 12.0 Hz, 1H), 2.43-2.42 (m, 1H), 2.19-2.07 (m, 1H), 1.99- 1.82 (m,2H).LC-MS: [M + H]⁺ = 548.3. 240

¹H NMR (400 MHz, CD₃OD) δ ppm 8.59 (s, 1H), 8.38 (m, 1H), 8.28-8.23 (m,1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.83-7.80 (t, J = 8.0 Hz, 1H), 7.66-7.64 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.33-7.31 (d, J = 7.6 Hz, 1H),5.68-5.81 (m, 2H), 3.64-3.61 (d, J = 11.2 Hz, 1H), 3.18-3.13 (m, 2H),3.04-3.00 (m, 1H), 2.32-2.27 (m, 1H), 2.10-2.06 (m, 1H), 1.86 (m, 2H).LC-MS: [M + H]⁺ = 549.2. 241

¹H NMR (400 MHz, CD₃OD) δ ppm 8.45 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H),7.79-7.55 (m, 2H), 7.55-7.35 (m, 2H), 7.18 (s, 1H), 7.04-6.72 (m, 2H),5.79-5.51 (m, 2H), 3.80 (s, 3H), 3.52 (d, J = 11.4 Hz, 1H), 3.13 (d, J =11.3 Hz, 2H), 3.03- 2.92 (m, 1H), 2.48 (d, J = 2.9 Hz, 3H), 2.24 (s,1H), 2.13-1.97 (m, 1H), 1.86 (tq, J = 8.3, 4.4 Hz, 2H). LC-MS: [M + H]⁺= 540.3, 541.3. 242

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H),7.88-7.80 (m, 1H), 7.70-7.65(d, J = 7.8 Hz, 1H), 7.53-7.44 (dt, J = 2.3,8.7 Hz, 1H), 7.36-7.30 (m, 1H), 7.05 (s, 1H), 7.02-6.95 (m, 1H),5.73-5.58 (m, 2H), 3.91 (s, 3H), 3.67-6.64 (m, 1H), 3.26-3.15(m, 2H),3.10- 3.00 (m, 1H), 2.38-2.25 (m, 1H), 2.20-2.06 (m, 1H), 1.95-1.90 (m,2H). LC-MS: [M + H]⁺ = 578.3. 243

¹H NMR (400 MHz, CD₃OD) δ ppm 7.25 (s, 1 H) 7.02 (d, J = 9.95 Hz, 1 H)6.94 (s, 1 H) 6.92 (s, 1 H) 6.73 (d, J = 12.35 Hz, 1 H) 6.57 (t, J =7.51 Hz, 1H) 6.45 (s, 1 H) 6.40 (d, J = 7.55 Hz, 1 H) 6.08 (d, J = 7.82Hz, 1 H) 4.31-4.41 (m, 2 H) 2.68- 2.72 (m, 3 H) 2.36 (br d, J = 11.49Hz, 1 H) 1.90- 1.99 (m, 2 H) 1.72-1.82(m, 1 H) 1.00-1.08(m, 1H)0.78-0.90 (m, 1 H). LC-MS: [M + H]⁺ = 561.3. 244

¹H NMR (400 MHz, DMSO-d₆ ) δ ppm 8.42 (s, 1H), 8.23 (s, 1H), 8.10 (s,1H), 7.85-7.79 (m, 2H), 7.78-7.73 (m, 1H), 7.69 (m, 1H), 7.34 (d, J =8.0 Hz, 1H), 7.23 (s, 3H), 5.57-5.36 (m, 2H), 3.05-2.78 (m, 4H),2.19-1.91 (m, 2H), 1.64 (m, 2H). LC-MS: [M + H]⁺ = 547.3. 245

¹H NMR (400 MHz, CD₃OD) δ ppm 8.65-8.42 (m, 3H), 8.25 (d, J = 2.4 Hz,2H), 7.84-7.63 (m, 3H), 7.60-7.47 (m, 1H), 7.39-7.20 (m, 2H), 5.67 (q, J= 16.3 Hz, 2H), 3.49 (d, J = 11.4 Hz, 1H), 3.16 (dd, J = 24.6, 11.6 Hz,2H), 3.04 (dt, J = 11.3, 5.6 Hz, 1H), 2.24-1.96 (m, 2H), 1.86 (ddd, J =32.2, 9.6, 4.8 Hz, 2H). LC-MS: [M + H]⁺ = 514.0, 515.0. 246

¹H NMR (400 MHz, CD₃OD) δ ppm 8.59 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H),8.25 (s, 2H), 7.85-7.72 (m, 2H), 7.67 (dd, J = 5.4, 1.6 Hz, 1H), 7.55(t, J = 5.9 Hz, 1H), 7.39-7.20 (m, 2H), 5.84-5.57 (m, 2H), 3.47 (d, J =11.3 Hz, 1H), 3.21-2.92 (m, 3H), 2.22-1.96 (m, 2H), 1.86 (dt, J = 20.8,9.4 Hz, 2H). LC-MS: [M + H]⁺ = 547.9, 549.0. 247

¹H NMR (400 MHz, CD₃OD) δ ppm 8.58 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H),8.25 (d, J = 4.9 Hz, 2H), 7.77 (ddd, J = 11.9, 7.8, 2.1 Hz, 1H),7.65-7.44 (m, 3H), 7.41-7.18 (m, 2H), 5.87-5.53 (m, 2H), 3.60-3.42 (m,1H), 3.16 (t, J = 11.3 Hz, 2H), 3.07-2.90 (m, 1H), 2.25-1.97 (m, 2H),1.97- 1.75 (m, 2H). LC-MS: [M + H]⁺ = 528.0, 529.0. 248

¹H NMR (400 MHz, CD₃OD) δ ppm 8.56 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H),8.23 (d, J = 4.9 Hz, 2H), 7.54-7.51 (m, 1H), 7.65-7.44 (m, 3H), 7.3-7.25(m, 2H), 5.68-5.59 (m, 2H), 3.67 (m, 1H), 3.3 (m,1H), 3.12-3.0 (m, 2H),2.3-2.0 (m, 2H), 1.93- 1.87 (m, 2H). LC-MS: [M + H]⁺ = 532.0, 532.9. 249

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.22 (s, 2H), 8.06 (d, J = 9.1Hz, 1H),7.81 (d, J = 9.1 Hz, 1H), 7.75 (ddd, J = 12.0, 7.8, 2.1 Hz, 1H),7.57-7.48 (m, 1H), 7.34-7.22 (m, 2H), 5.61 (s, 2H), 3.72 (d, J = 11.5Hz, 1H), 3.28 (s, 1H), 3.17- 3.08 (m, 1H), 3.05-2.92 (m, 1H), 2.34 (d, J= 12.0 Hz, 1H), 2.16-2.04 (m, 1H), 1.94 (dd, J = 8.4, 5.0 Hz, 1H), 1.82(dd, J = 9.3, 4.5 Hz, 1H). LC-MS: [M + H]⁺ = 548.7. 250

¹H NMR (400 MHz, CD₃OD) δ ppm 8.73 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H),8.20 (d, J = 19.5 Hz, 2H), 7.89-7.61 (m, 2H), 7.24 (s, 1H), 7.21-7.01(m, 2H), 5.79-5.47 (m, 2H), 3.62 (d, J = 11.3 Hz, 1H), 3.24-3.08 (m,2H), 3.01 (t, J = 10.7 Hz, 1H), 2.87 (q, J = 7.6 Hz, 2H), 2.33 (t, J =11.0 Hz, 1H), 2.09 (dt, J = 14.0, 6.8 Hz, 1H), 1.95-1.79 (m, 2H), 1.32(t, J = 7.6 Hz, 3H). LC-MS: [M + H]⁺ = 525.3, 526.3. 251

¹H NMR (400 MHz, CD₃OD) δ ppm 8.67 (d, J = 5.4 Hz, 1H), 8.52 (s, 1H),8.21 (d, J = 12.9 Hz, 2H), 7.73 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.65-7.46 (m, 2H), 7.40-7.03 (m, 2H), 5.81-5.43 (m, 2H), 3.62 (d, J = 11.2Hz, 1H), 3.14 (t, J = 10.2 Hz, 2H), 2.96 (p, J = 7.6 Hz, 3H), 2.29 (t, J= 10.8 Hz, 1H), 2.08 (dq, J = 12.0, 7.5, 6.8 Hz, 1H), 1.93- 1.72 (m,2H), 1.34 (t, J = 7.6 Hz, 3H). LC-MS: [M + H]⁺ = 543.5, 544.4. 252

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.28 (s, 1H), 7.68-7.73 (m, J =7.9 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 6.0 Hz, 1H), 6.60(d, J = 7.7 Hz, 1H), 6.46 (s, 1H, 5.53 (d, J = 9.4 Hz, 2H), 3.57 (d, J =11.4 Hz, 1H), 3.10 (t, J = 11.5 Hz, 2H), 2.92 (td, J = 11.6, 10.5, 3.0Hz, 1H), 2.78 (t, 2H), 2.30 (b, 1H), 2.10 (b, 1H), 1.97-1.75 (m, 3H),1.28 (t, 3H), 0.94-0.80 (m, 2H), 0.79-0.65 (m, 2H). LC-MS: [M + H]⁺ =469.0, 470.0. 253

¹H NMR (CD₃OD) δ: 9.10 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 8.21 (d, J =12.6 Hz, 2H), 8.06 (dd, J = 8.8, 1.5 Hz, 1H), 7.88-7.64 (m, 2H), 7.53(s,1H), 7.42-7.09 (m, 2H), 5.62 (s, 2H), 3.75 (d, J = 11.7 Hz, 1H),3.20-2.85 (m, 3H), 2.37 (s, 2H), 2.02- 1.69 (m, 2H) LCMS: [M + H]⁺ =514.9. 254

¹H NMR (CD₃OD) δ: 8.89 (s, 1H), 8.57 (d, J = 10.5 Hz, 2H), 8.21 (d, J =7.0 Hz, 2H), 7.89-7.70 (m, 1H), 7.53 (s, 1H), 7.29 (d, J = 15.7 Hz, 2H),5.85-5.31 (m, 2H), 3.64 (d, J = 11.4 Hz, 1H), 3.16-3.01 (m, 3H),2.42-2.04 (m, 2H), 2.00- 1.74 (m, 2H) LC-MS: [M + H]⁺ = 549.2 255

¹H NMR (400 MHz, CD₃OD) δ ppm 9.16 (s, 1H), 8.77 (d, J = 5.6 Hz, 1H),8.53 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H),7.76-7.71 (m, 1H), 7.54-7.52 (m, 1H), 7.32 (s, 1H), 7.27- 7.23 (m, 1H),5.66-5.57 (m, 2H), 3.63 (d, J = 11.2 Hz, 1H), 3.19 (d, J = 11.2 Hz, 1H),3.13-3.09 (m, 1H), 3.02-2.97 (m, 1H), 2.31-2.26 (m, 1H), 2.09- 2.03 (m,1H), 1.88-1.81 (m, 2H). LC-MS: [M + H]⁺ = 515.1. 256

¹H NMR (400 MHz, CD₃OD) δ ppm 8.73 (s, 1H), 8.53 (s, 1H), 8.40 (s, 1H),8.19 (s, 1H), 7.68 (ddd, J = 7.1, 5.3, 1.7 Hz, 3H), 7.15-7.04 (m, 2H),7.01 (s, 1H), 6.60 (d, J = 6.0 Hz, 1H), 5.64 (t, J = 12.5 Hz, 2H), 3.69(d, J = 11.4 Hz, 1H), 3.21 (d, J = 11.4 Hz, 2H), 3.02 (ddd, J = 12.0,9.6, 2.9 Hz, 1H), 2.87 (q, J = 7.6 Hz, 2H), 2.39 (t, J = 10.0 Hz, 1H),2.16 (td, J = 12.4, 9.7, 5.7 Hz, 1H), 1.91 (t, J = 9.9 Hz, 2H),1.35-1.30 (m, 3H). LC-MS: [M + H]⁺ = 524.3, 525.3. 257

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.21 (d, J = 15.3 Hz, 2H),7.78 (td, J = 8.8, 6.5 Hz, 1H), 7.15-6.71 (m, 3H), 6.05 (td, J = 55.4,4.4 Hz, 1H), 5.69 (s, 2H), 3.99 (s, 1H), 3.25 (d, J = 1.6 Hz, 1H),3.13-2.91 (m, 3H), 1.89 (d, J = 16.2 Hz, 3H), 1.65 (s, 1H). LC-MS: [M +H]⁺ = 529.3, 530.3. 258

¹H NMR (400 MHz, CD₃OD) δ ppm 8.71 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1H),8.20 (d, J = 17.0 Hz, 2H), 7.73 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.57-7.46(m, 1H), 7.41-7.14 (m, 2H), 5.74-5.45 (m, 2H), 3.62 (d, J = 11.4 Hz,1H), 3.16 (dd, J = 15.7, 11.5 Hz, 2H), 3.06-2.89 (m, 1H), 2.56 (s, 3H),2.32 (t, J = 10.4 Hz, 1H), 2.18-2.02 (m, 1H), 1.96-1.79 (m, 2H). LC-MS:[M + H]⁺ = 528.8, 529.8. 259

¹H NMR (400 MHz, CD₃OD): δ 8.95 (1H, s), 8.65 (1H, s), 8.54 (1H, s),8.51 (1H, s), 8.23 (1H, s), 8.20 (1H, s), 7.70-7.80 (1H, m), 7.45-7.56(1H, m), 7.25-7.35 (2H, m), 5.45-5.80 (2H, m), 3.55- 3.65 (1H, m),3.10-3.25 (2H, m), 2.90-3.05 (1H, m), 2.25-2.40 (1H, m), 2.05-2.20 (1H,m), 1.75- 1.90 (2H, m). LC-MS: [M + H]⁺ = 515.2. 260

¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1H), 8.16 (s, 1H), 7.98 (t, J =7.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72-7.62 (m, 2H), 7.57 (d, J =7.7 Hz, 1H), 7.48-7.37 (m, 1H), 7.24 (dt, J = 10.3, 8.4 Hz, 1H), 7.07(s, 1H), 6.88-6.52 (m, 2H), 5.59 (t, J = 12.3 Hz, 2H), 3.70 (d, J = 11.4Hz, 1H), 3.20 (t, J = 9.4 Hz, 2H), 3.07-2.94 (m, 1H), 2.37 (t, J = 10.6Hz, 1H), 2.21-2.05 (m, 1H), 2.01-1.83 (m, 2H). LC-MS: [M + H]⁺ = 563.3,564.2. 261

¹H NMR (CD₃OD) δ: 8.51 (s, 1H), 8.15 (s, 1H), 7.68 (ddd, J = 7.7, 6.4,3.6 Hz, 4H), 7.45 (d, J = 7.9 Hz, 1H), 7.22-6.96 (m, 4H), 6.62 (d, J =6.0 Hz, 1H), 5.81-5.48 (m, 2H), 3.63 (d, J = 11.2 Hz, 1H), 3.33 (p, J =1.6 Hz, 1H), 3.22-3.15 (m, 1H), 2.97 (ddd, J = 11.9, 9.3, 2.8 Hz, 1H),2.51 (s, 3H), 2.38-2.25 (m, 1H), 2.17-2.09 (m, 1H), 1.90 (ddt, J = 19.9,13.6, 4.8 Hz, 2H) LC-MS: [M + H]⁺ = 509.0 262

¹H NMR (400 MHz, CD₃OD) δ ppm 8.57 (s, 1H), 8.20(s, 1H), 7.96 (q, J =8.1 Hz, 1H), 7.79-7.50 (m, 3H), 7.51-7.38 (m, 1H), 7.27 (dt, J = 10.4,8.5 Hz, 1H), 7.09 (s, 1H), 6.96 (dd, J = 8.2, 2.8 Hz, 1H), 6.60 (d, J =6.1 Hz, 1H), 5.77-5.53 (m, 2H), 3.67 (d, J = 11.4 Hz, 1H), 3.25-3.11 (m,2H), 3.08-2.94 (m, 1H), 2.35 (t, J = 10.5 Hz, 1H), 2.23-2.06 (m, 1H),1.91 (td, J = 12.1, 10.2, 5.6 Hz, 2H). LC-MS: [M + H]⁺ = 531.0, 532.0.263

¹H NMR (400 MHz, CD₃OD): δ 8.28 (s, 1H), 8.10 (s, 1H), 7.73-7.65 (m,2H), 7.45 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.59 (d, J =6.0 Hz, 1H), 6.46 (s, 1H), 5.60-5.45 (m, 2H), 3.57 (d, J = 10.8 Hz, 1H),3.17-3.03 (m, 2H), 2.92 (t, J = 9.6 Hz, 1H), 2.52 (s, 3H), 2.37-2.24 (m,1H), 2.15- 2.03 (m, 1H), 1.97-1.80 (m, 3H), 0.93-0.84 (m, 2H), 0.77-0.70(m, 2H). LC-MS: [M + H]⁺ = 455.3 264

¹H NMR (CD₃OD) δ: 8.28 (s, 1H), 8.10 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H),7.81 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 7.7 Hz,1H), 6.87-6.48 (m, 2H), 6.43 (s, 1H), 5.49 (d, J = 9.4 Hz, 2H), 3.60 (d,J = 11.4 Hz, 1H), 3.10 (t, J = 11.6 Hz, 2H), 2.92 (td, J = 11.7, 10.5,3.1 Hz, 1H), 2.33 (s, 1H), 2.16-2.03 (m, 1H), 1.99-1.64 (m, 3H),0.92-0.81 (m, 2H), 0.78-0.65 (m, 2H) LC- MS: [M + H]⁺ = 491.0 265

¹H NMR (400 MHz, CD₃OD): δ 8.18 (s, 1H), 7.87- 7.83 (m, 1H), 7.73-7.65(m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 5.2 Hz, 1H), 5.92 (s,1H), 4.24 (t, J = 5.6 Hz, 2H), 3.61-3.47 (m, 1H), 3.38 (t, J = 5.6 Hz,2H), 3.24-3.10 (m, 1H), 3.02 (d, J = 11.2 Hz, 1H), 2.88 (t, J = 9.6 Hz,1H), 2.39-2.23 (m, 1H), 2.15-2.10 (m, 3H), 1.91-1.86 (m, 2H). LC-MS:[M + H]⁺ = 490.1 266

¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J = 4.4 Hz, 1H), 8.53 (s, 1H), 8.25(s, 1H), 7.88-7.70 (m, 4H), 7.61 (d, J = 6.0 Hz, 1H), 7.32-7.26 (m, 1H),7.22 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.54 (d, J = 5.6 Hz, 1H), 6.24(brs, 2H), 5.58 (m, 2H), 3.62-3.50 (m, 1H), 3.17-3.06 (m, 2H), 2.95-2.85(m, 1H), 2.38-2.06 (m, 2H), 1.88-1.73 (m, 2H). LC-MS: [M + H]⁺ = 495.3267

¹H NMR (400 MHz, CD₃OD) δ ppm 8.40 (s, 1H), 8.16 (s, 1H), 7.83 (t, J =7.6 Hz, 1H), 7.75-7.65 (m, 2H), 7.34 (d, J = 7.2 Hz, 1H), 6.56 (d, J =6.0 Hz, 1H), 6.51 (s, 1H), 5.65-5.50 (m, 2H), 3.75- 3.60 (m, 1H),3.55-3.40 (m, 1H), 3.20-2.95 (m, 3H), 2.43-1.70 (m, 10H).LC-MS: [M + H]⁺= 489.2. 268

¹H NMR (400 MHz, CD₃OD): δ 8.28 (s, 1H), 8.12 (s, 1H), 7.81 (t, J = 8.0Hz, 1H), 7.72-7.58 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 6.0Hz, 1H), 6.43 (s, 1H), 5.60-5.43 (m, 2H), 3.69-3.55 (m, 1H), 3.18-3.01(m, 2H), 2.97-2.88 (m, 1H), 2.39-2.25 (m, 1H), 2.13-1.98 (m, 1H),1.90-1.79 (m, 3H), 0.92-0.84 (m, 2H), 0.77-0.69 (m, 2H). LC-MS: [M + H]⁺= 475.1 269

¹H NMR(DMSO 400 MHz): δ 8.49 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H),7.80-7.90 (m, 1H), 7.66 (s, 1H), 7.60-7.65 (m, 1H), 7.40-7.55 (m, 2H),7.33 (s, 1H), 7.28 (brs, 2H), 5.45-5.65 (m, 2H), 3.77 (s. 3H), 3.00-3.10(m, 3H), 3.80-3.90 (m, 1H), 1.95- 2.05 (m, 1H), 1.65-1.85 (m, 3H).LC-MS: [M + H]⁺ = 517.2. 270

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.23 (d, J = 13.8 Hz, 2H),7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.54(ddd, J = 9.2, 4.3, 2.2 Hz, 1H), 7.29 (d, J = 9.3 Hz, 2H), 5.78-5.49 (m,2H), 3.88 (s, 3H), 3.27 (s, 1H), 3.19 (d, J = 11.3 Hz, 1H), 3.10 (d, J =11.8 Hz, 1H), 3.02-2.87 (m, 1H), 2.13-1.87 (m, 3H), 1.82 (dq, J = 12.2,4.0 Hz, 1H). LC-MS: [M + H]⁺ = 516.3. 271

¹H NMR (CDCl₃ 400 MHz): δ 8.85 (s, 1H), 8.56 (s, 1H), 8.46 (d, J = 4.4Hz, 1H), 8.23 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.76-7.70 (m, 1H),7.53-7.50 (m, 1H), 7.48 (dd, J = 4.8 Hz and 8.0 Hz, 1H), 7.30 (s, 1H),7.28-7.22 (m, 1H), 5.69 (d, J = 18 Hz, 1H), 5.62 (d, J = 18 Hz, 1H),3.48 (d, J = 11.8 Hz, 2H), 3.24 (d, J = 11.6 Hz, 2H), 3.11 (d, J = 11.2Hz, 1H), 3.01 (t, J = 10.8 Hz, 1H), 2.16-2.08 (m, 2H), 1.96-1.93 (m,1H), 1.84-1.79 (m, 2H). LCMS: [M + H]⁺ = 514.1 272

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H),7.85-7.83 (m, 2H), 7.78-7.73 (m, 1H), 7.54-7.50 (m, 1H), 7.36 (s, 1H),7.32-7.28 (m, 1H), 6.52-6.49 (t, J1 = 6.8 Hz, 1H), 5.68 (s, 2H),3.77-3.74 (m, 1H), 3.38-3.35 (m, 1H), 3.17-3.14 (m, 1H), 3.04-2.99 (m,1H), 2.27-2.07 (m, 3H), 1.96-1.93 (m, 1H). LC-MS: [M + H]⁺ = 530.4. 273

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H),8.00 (d, J = 2.8 Hz, 1H), 7.81-7.70 (m, 2H), 7.45 (t, J = 59.9 Hz, 1H),7.25 (s, 1H), 7.13 (t, J = 8.8 Hz, 2H), 8.87 (d, J = 2.8 Hz, 1H), 5.63(s, 2H), 3.51 (d, J = 11.5 Hz, 1H), 3.15 (dd, J = 19.7, 9.0 Hz, 2H),2.97 (t, J = 10.2 Hz, 1H), 2.26-2.10 (m, 1H), 2.03 (s, 1H), 1.97-1.77(m, 2H). LC-MS: [M + H]⁺ = 535.3, 536.3. 274

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (t, J = 6.3 Hz, 1H), 8.33-8.14 (m,1H), 8.06 (s, 1H), 7.78 (ddd, J = 8.7, 5.5, 3.0 Hz, 2H), 7.58 (tt, J =6.3, 2.9 Hz, 1H), 7.30 (dd, J = 8.0, 4.9 Hz, 1H), 7.13 (td, J = 8.5, 5.6Hz, 2H), 6.38 (td, J = 8.1, 2.8 Hz, 1H), 5.76-5.48 (m, 2H), 4.48 (dt, J= 9.4, 4.9 Hz, 1H), 3.46 (d, J = 11.4 Hz, 1H), 3.14 (dd, J = 11.4, 6.0Hz, 2H), 2.95 (d, J = 10.9 Hz, 1H), 2.17 (s, 1H), 2.03 (s, 1H),1.96-1.79 (m, 2H), 1.43 (q, J = 7.2, 8.7 Hz, 6H). LC-MS: [M + H]⁺ =527.3, 528.3. 275

¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H),7.77 (ddd, J = 12.0, 7.8, 2.3 Hz, 1H), 7.65-7.46 (m, 2H), 7.39 (s, 1H),7.31 (dt, J = 10.4, 8.5 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 5.86-5.36 (m,2H), 3.87 (s, 3H), 3.58-3.42 (m, 1H), 3.17(t, J = 10.8 Hz, 2H),3.07-2.84 (m, 1H), 2.19 (dd, J = 23.5, 9.1 Hz, 1H), 2.06 (dd, J = 10.4,4.1 Hz, 1H), 1.92(q, J = 11.0, 9.3 Hz, 2H). LC-MS: [M + H]⁺ = 517.0,518.0. 276

¹H NMR (400 MHz, CD₃OD) δ ppm 8.41-8.18 (m, 1H), 8.05 (s, 1H), 7.79-7.41(m, 2H), 6.62 (d, J = 5.9 Hz, 1H), 6.50 (d, J = 4.6 Hz, 1H), 6.37 (d, J= 3.1 Hz, 1H), 5.67-5.41 (m, 2H), 4.13 (ddd, J = 13.9, 9.0, 5.2 Hz, 2H),3.40 (s, 1H), 3.07 (s, 2H), 2.86 (s, 1H), 2.10 (d, J = 66.2 Hz, 2H),1.96-1.73(m, 2H), 1.37-1.28(m, 4H), 0.99-0.66 (m, 4H). LC-MS: [M + H]⁺ =458.3, 459.4. 277

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.13 (s, 1H), 7.75-7.64 (m,3H), 7.59 (d, J = 2.0 Hz, 1H), 7.16-7.05 (m, 3H), 6.67 (d, J = 5.6 Hz,1H), 6.41 (d, J = 2.0 Hz, 1H), 5.77-5.68 (m, 1H), 5.65-5.53 (m, 1H),4.14 (q, J = 7.2 Hz, 2H), 3.57-3.46 (m, 1H), 3.25-3.14 (m, 2H),3.03-2.92 (m, 1H), 2.32-2.19 (m, 1H), 2.16-2.04 (m, 1H), 2.02-1.83 (m,2H), 1.39 (t, J = 7.2 Hz, 3H). LC- MS: [M + H]⁺ = 512.3. 278

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.23 (s, 1H), 8.08 (br.s,1H), 7.77-7.72 (m, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 6.8 Hz,1H), 7.36 (s, 1H), 7.32-7.25 (m, 1H), 6.36 (d, J = 2.3 Hz, 1H),5.69-5.59 (m, 2H), 3.61-3.55 (m, 1H), 3.46 (d, J = 11.5 Hz, 1H), 3.14(d, J = 11.5 Hz, 2H), 2.94 (t, J = 9.5 Hz, 1H), 2.18-2.14 (m, 1H),2.06-2.00 (m, 1H), 1.91-1.87 (m, 2H), 1.06- 0.96 (m, 4H).LC-MS: [M + H]⁺= 543.1 . 279

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.14 (s, 1H), 8.01 (d, J =2.7 Hz, 1H), 7.74- 7.61 (m, 3H)' 7.43 (t, J = 59.8 Hz, 1H), 7.09 (dd, J= 17.5, 8.6 Hz, 3H), 6.65 (dd, J = 19.9, 4.4 Hz, 2H), 5.74-5.47 (m, 2H),3.56 (d, J = 11.4 Hz, 1H), 3.18 (d, J = 11.2 Hz, 2H), 2.96 (t, J = 9.0Hz, 1H), 2.26 (dd, J = 27.5, 15.2 Hz, 1H), 2.06 (s, 1H), 1.98-1.83 (m,2H). LC-MS: [M + H]⁺ = 534.3, 535.3. 280

¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1H), 8.12 (s, 1H), 7.71-7.66 (m,3H), 7.58 (d, J = 2.3 Hz, 1H), 7.10 (t, J = 9.6 Hz, 3H), 6.66 (d, J =6.0 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 5.73-5.56 (m, 2H), 3.58-3.49 (m,2H), 3.19-3.12 (m, 2H), 2.98-2.93 (t, J = 8.8 Hz, 1H), 2.25-2.20 (m,1H), 2.09-2.04 (m, 1H), 1.94-1.85 (m, 2H), 1.02-0.93 (m, 4H).LC-M5: [M +H]⁺ = 524.1 281

¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H),7.77-7.73 (m, 2H), 7.52 (s, 1H), 7.24 (s, 1H), 7.15-7.10 (m, 2H),5.67-5.56 (m, 2H), 3.52-3.49 (m, 1H), 3.21-3.17 (m, 1H), 3.12-3.08 (m,1H), 3.02-2.97 (m, 1H), 2.26-2.21 (m, 1H), 2.07-1.99 (m, 1H), 1.92-1.83(m, 2H). LCMS: 536.3 [M + H]⁺ = 536.3 282

¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H),7.98 (s, 1H), 7.73 (ddd, J = 2 Hz, 7.6 Hz, 11.6 Hz, 1H), 7.55-7.50 (m,1H), 7.31-7.23 (m, 2H), 5.66-5.56 (m, 2H), 4.09 (s, 3H), 3.49 (d, J =11.2 Hz, 1H), 3.23 (d, J = 11.2 Hz, 1H), 3.12-3.05 (m, 1H), 3.02-2.95(m, 1H), 2.25-2.15 (m, 1H), 2.09-1.99 (m, 1H), 1.96- 1.89 (m, 1H),1.86-1.78 (m, 1H). LC-MS: [M + H]⁺ = 518.1. 283

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H),7.74 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.53 (ddd, J = 8.0, 4.1, 2.0 Hz,1H), 7.35 (s, 1H), 7.28 (dt, J = 10.4, 8.4 Hz, 1H), (s, 1H), 5.61 (s,2H), 3.46 (d, J = 11.4 Hz, 1H), 3.22 (d, J = 11.3 Hz, 1H), 3.12-3.05 (m,1H), 2.97 (td, J = 11.8, 10.5, 3.2 Hz, 1H), 2.40 (s, 3H), 2.28-2.08 (m,1H), 2.03 (d, J = 11.7 Hz, 1H), 1.98-1.80 (m, 2H). LC-MS: [M + H]⁺ =517.8, 518.8. 284

¹H NMR (400 MHz, CD₃OD) δ ppm 8.52 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H),7.74 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.53 (ddd, J = 8.0, 4.1, 2.0 Hz,1H), 7.35 (s, 1H), 7.28 (dt, J = 10.4, 8.4 Hz, 1H), 6.31 (s, 1H), 5.61(s, 2H), 3.46 (d, J = 11.4 Hz, 1H), 3.22 (d, J = 11.3 Hz, 1H), 3.12-3.05(m, 1H), 2.97 (td, J = 11.8, 10.5, 3.2 Hz, 1H), 2.40 (s, 3H), 2.28-2.08(m, 1H), 2.03 (d, J = 11.7 Hz, 1H), 1.98-1.80 (m, 2H). LC-MS: [M + H]⁺ =517.8, 518.8.

Examples 285-291 were prepared following procedures analogous to thosedescribed in Example 47 from corresponding intermediates.

Example # Structure ¹H NMR & MS 285

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.20 (d, J = 10.0 Hz, 2H),7.75-7.66 (m, 1H), 7.49 (s, 1H), 7.24 (d, J = 10.2 Hz, 2H), 5.69-5.53(m, 2H), 4.40 (s, 1H), 3.96-3.73 (m,2H), 3.15 (d, J = 11.5 Hz, 1H), 2.98(d, J = 11.3 Hz, 2H), 2.85 (t, J = 10.7 Hz, 1H), 1.92 (s, 1H), 1.75 (d,J = 12.0 Hz, 2H), 1.67 (s, 1H). LC- MS: [M + H]⁺ = 499.2. 286

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.21 (d, J = 11.9 Hz, 2H), 7.78(ddd, J = 11.5, 9.1,7.1 Hz, 1H), 7.17 (td, J = 10.5, 6.6 Hz, 1H), 7.13-7.11 (m, 1H),5.71-5.63 (m, 2H),4.62-4.43 (m, 1H), 4.01-3.81 (m, 2H),3.21 (d, J = 11.3 Hz, 1H), 3.13-3.03 (m, 2H), 2.93 (t, J = 10.6 Hz, 1H),2.08-1.96 (m, 1H), 1.82 (t, J = 10.7 Hz, 2H), 1.71 (d, J = 11.7 Hz, 1H).[M + H]⁺ = 517.1 287

¹H NMR: (400 MHz, CD₃OD): δ 8.53-8.48 (m, 1H), 8.26-8.19 (m, 2H),7.78-7.70 (m, 1H), 7.57-7.50 (m, 1H), 7.34-7.23 (m, 2H), 5.70- 5.59 (m,2H), 3.18 (br d, J = 11.1 Hz, 1H), 3.07- 2.85 (m, 3H), 2.02-1.88 (m,1H), 1.87-1.71 (m, 2H), 1.70-1.54 (m, 1H). LC-MS: [M + H]⁺ = 501.4. 288

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.23 (s, 2H), 7.76 (m, 1H),7.54 (m, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 5.74-5.55 (m, 2H), 3.85 (m,1H), 3.77-3.65 (m, 2H), 3.63-3.56 (m, 1H), 3.55-3.47 (m, 1H), 3.17-3.07(m, 2H), 3.01 (m, 1H), 2.95 (m, 1H), 2.91-2.79 (m, 1H), 2.00-1.86 (m,1H), 1.83-1.70 (m, 2H), 1.69-1.57 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H). LC-MS: [M + H]⁺ = 537.4 285

¹H NMR (400 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 8.20 (d, J = 10.0 Hz, 2H),7.75-7.66 (m, 1H), 7.49 (s, 1H), 7.24 (d, J = 10.2 Hz, 2H), 5.69-5.53(m, 2H), 4.40 (s, 1H), 3.96-3.73 (m,2H), 3.15 (d, J = 11.5 Hz, 1H), 2.98(d, J = 11.3 Hz, 2H), 2.85 (t, J = 10.7 Hz, 1H), 1.92 (s, 1H), 1.75 (d,J = 12.0 Hz, 2H), 1.67 (s, 1H). LC- MS: [M + H]⁺ = 499.2. 290

¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1H), 8.20 (s, 2H), 7.82-7.75 (m,1H), 7.21-7.09 (m, 2H), 5.68-5.62 (m, 2H), 3.91-3.81 (m, 2H), 3.78-3.54(m, 5H), 3.19-3.11 (m, 2H), 3.00-2.97 (M, 1H), 2.91-2.86 (m,1H). LC-MS:[M + H]⁺ = 541.4. 291

¹H NMR (, 400 MHz, CD₃OD): δ 8.64 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H),7.65-7.60 (m, 1H), 7.44-7.40 (m, 1H), 7.09 (s, 1H), 7.01-6.74 (d, J1 =54.8 Hz, J2 = 109.6 Hz, 1H), 5.72-5.62 (m, 2H), 4.00-3.95 (m, 2H),3.84-3.60 (m, 5H), 3.45- 3.42 (m, 1H), 3.35 (m, 1H), 3.13-3.10 (m, 1H),2.99-2.90 (m, 1H), 2.05-1.85 (m, 4H). [M + H]⁺ = 573.4 292

¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 8.36 (brs, 1H), 8.26 (s, 1H),8.14 (s, 1H), 7.90- 7.80 (m, 1H), 7.65-7.57 (m, 1H), 7.46 (t, J = 8.8Hz, 1H), 7.35-7.25 (m, 3H), 5.53 (s, 2H), 4.24 (d, J = 8.4 Hz, 1H), 4.07(d, J = 8.8 Hz, 1H), 3.15-3.03 (m, 2H), 2.95-2.80 (m, 2H), 1.85-1.77 (m,1H), 1.76-1.60 (m, 3H). LC-MS: [M + H]⁺ = 493.2. 293

¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.22 (d, J = 1.7 Hz, 2H),7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H),7.39-7.07 (m, 2H), 6.00-5.41 (m, 2H), 3.25 (s, 1H), 3.13 (d, J = 11.3Hz, 1H), 2.95 (dt, J = 20.7, 11.5 Hz, 2H), 2.10-1.79(m, 3H), 1.71 (t, J= 3.4 Hz, 4H). LC-MS: [M + H]⁺ = 513.3, 514.3. 294

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.21 (s, 2H), 7.78-7.70 (m,1H), 7.57-7.49 (m, 1H), 7.35-7.25 (m, 2H), 5.72-5.55 (m, 2H), 4.70-4.60(m, 1H), 3.20-2.90 (m, 4H), 2.00-1.70 (m, 4H). LC-MS: [M + H]+ = 499.2.295

¹H NMR (400 MHz, CD₃OD) δ ppm 8.48 (s, 1H), 8.26 (s, 2H), 7.69-7.35 (m,2H), 7.23 (s, 1H), 7.13 (t, J = 8.6 Hz, 1H), 5.88-5.54 (m, 2H), 3.90 (s,3H), 3.21-2.87 (m, 4H), 1.93 (dt, J = 9.1, 4.4 Hz, 1H), 1.78-1.48 (m,3H), 1.39 (dd, J = 25.1, 6.4 Hz, 4H). LC-MS: [M + H]⁺ = 495.2, 496.2.296

¹H NMR (400 MHz, CDCl₃) δ ppm 8.49 (s, 1H), 8.39 (s, 1H), 7.92 (s, 1H),7.70-7.65 (m, 1H), 7.51 (s, 1H), 7.49-7.40 (m, 1H), 7.20-7.10 (m, 2H),6.26 (s, 1H), 5.70-5.60 (m, 3H), 5.48 (d, J = 16 Hz, 1H), 4.45-4.35 (m,1H), 4.19 (d, J = 14 Hz, 1H), 3.05-2.30 (m, 4H), 1.95-1.50 (m, 4H).LC-MS: [M + H]⁺ = 517.3. 297

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.50 (s, 1H), 8.30 (s, 1H), 8.13 (s,1H), 7.90-7.80 (m, 1H), 7.63-7.55 (m, 1H), 7.52-7.42 (m, 1H), 7.36 (s,1H), 7.28 (brs, 2H), 5.55 (s, 2H), 2.98-2.80 (m, 4H), 2.72 (s, 2H),1.90-1.75 (m, 3H), 1.73- 1.55 (m, 2H), 1.54-1.40 (m, 1H). LC-MS: [M +H]⁺ = 497.2. 298

¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H),7.95-7.82 (m, 1H), 7.65-7.60 (m, 1H), 7.51 (q, J = 8.8 Hz, 1H), 7.38 (s,1H), 7.30 (brs, 2H), 5.56 (s, 2H), 3.60- 3.40 (m, 2H), 3.11 (s, 3H),3.10-2.97 (m, 2H), 2.95-2.80 (m, 2H), 2.48-2.10 (m, 1H), 1.95-1.50 (m,4H). LC-MS: [M + H]⁺ = 529.2 299

¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H),7.76-7.70 (m, 1H), 7.56-7.50 (m, 1H), 7.35-7.22 (m, 2H), 7.23- 7.21 (m,1H), 5.75-5.55 (m, 2H), 4.34 (s, 1H), 3.30-3.13 (m, 1H), 3.00 (s, 3H),2.00-1.90 (m, 2H), 1.87-1.67 (m, 2H). LC-MS: [M + H]⁺ = 535.4. 300

¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J = 6.6 Hz, 1H), 8.27-8.20 (m, 2H),7.75 (ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.35- 7.23 (m,2H), 6.45-6.08 (m, 1H), 5.64 (d, J = 3.4 Hz, 2H), 4.89-4.41 (m, 1H),3.21 (d, J = 11.4 Hz, 1H), 3.07-2.82 (m, 3H), 2.04-1.60 (m, 4H). LC-MS:[M + H]⁺ = 519.2.

Example 301:3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol

To a solution of Intermediate B (104 mg, 0.311 mmol) and intermediate301-8 (130 mg, 0.311 mmol) in DMF (10 mL) was added K₂CO₃ (215 mg, 1.556mmol) at rt under N₂ atmosphere, the reaction was stirred at RT for 18hr. The reaction mixture was diluted with water, extracted with EtOAc(20 ml*3), the combined organic phase was washed with water (20 mL*3),brine (20 ml), dried over anhydrous sodium sulfate, concentrated invacuum to give a residue. The residue was purified by flashchromatography (elution gradient: 0% to 10% MeOH in DCM in 30 mins) toafford intermediate 301-9. LC-MS: [M+H]⁺=311.1.

To a solution of intermediate 301-9 (60 mg, 0.084 mmol) in DCM (9 mL)was added TFA (3 ml, 38.9 mmol) at RT under N₂ atmosphere, the reactionwas stirred at RT for 2 hr. The reaction mixture was concentrated invacuum to give a residue. The residue was purified by Pre-HPLC (Basiccondition, NH₃H₂O %=0.05%, MeCN/H₂O=0-95% in 12 mins) to afford3-amino-1-(4-((6-amino-9H-purin-9-yl) methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol (Example 301). ¹H NMR(400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 7.82 (ddd,J=11.2, 8.1, 2.2 Hz, 1H), 7.63 (dt, J=5.8, 2.9 Hz, 1H), 7.47 (s, 1H),7.31 (dt, J=10.2, 8.4 Hz, 1H), 6.41 (tt, J=55.3, 4.7 Hz, 1H), 5.65 (s,2H), 3.94 (dd, J=10.4, 5.3 Hz, 1H), 3.50-3.38 (m, 2H), 3.11-22.93 (m,2H), 2.69-2.36 (m, 2H), 2.07 (dd, J=14.1, 4.8 Hz, 1H), 2.01-1.84 (m,1H). LC-MS: [M+H]+=517.2.

Examples 302-310 were prepared following procedures analogous to thepreparation of Example 47 and the corresponding intermediates.

Example # Structure ¹H NMR & MS 302

¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 9.3 Hz,2H), 7.83-7.68 (m, 3H), 7.52 (dddd, J = 8.6, 3.8, 2.2, 1.3 Hz, 1H),7.33-7.23 (m, 3H), 5.79-5.61 (m,2H), 4.39 (dd, J = 11.0, 5.1 Hz, 1H),3.57 (d, J = 11.8 Hz, 1H), 3.18 (ddd, J = 7.2, 5.6, 2.4 Hz, 1H), 3.11(td, J = 11.5, 2.7 Hz, 2H), 2.10-2.01 (m, 1H), 1.96 (ddt, J = 13.0, 5.7,3.0 Hz, 1H). [M + H]+ = 564.2. 303

¹H NMR (CD₃OD) δ 8.46 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.58 (dd, J =12.8, 2.2 Hz, 1H), 7.48 (dt, J = 8.6, 1.6 Hz, 1H), 7.27 (s, 1H), 7.11(t, J = 8.6 Hz, 1H), 5.81-5.51 (m, 2H), 3.89 (s, 3H), 3.15- 2.80 (m,4H), 2.68-2.35 (m, 2H), 1.93 (d, J = 11.3 Hz, 1H), 1.76 (dt, J = 11.9,6.4 Hz, 3H). LC- MS: [M + H]+ = 530.8. 304

¹H NMR (400 MHz, CD₃OD) δ ppm 8.49 (s, 1H), 8.26 (d, J = 29.8 Hz, 2H),7.73 (ddd, J = 11.3, 7.9, 2.0 Hz, 1H), 7.51 (q, J = 3.7 Hz, 1H), 7.43-7.12 (m, 2H), 5.95-5.47 (m, 2H), 3.35 (d,J = 11.6 Hz, 1H), 3.12 (d, J =11.4 Hz, 1H), 3.01 (t, J = 9.8 Hz, 1H), 2.90 (d, J = 11.3 Hz, 1H), 2.84(s, 1H), 1.98 (dd, J = 59.1, 12.9 Hz, 3H), 1.69 (t, J = 11.5 Hz, 1H).LC-MS: [M + H]+ = 461.2, 462.2. 305

¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H),7.71 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.29(brs, 2H), 7.24 (t, J = 8.8 Hz, 1H), 6.04 (t, J = 16.8 Hz, 1H), 5.53 (s,2H), 3.86 (s, 3H), 3.05- 2.80 (m, 4H), 2.05-1.85 (m, 3H), 1.75-1.60 (m,2H), 1.55-1.43 (m, 1H). LC-MS: [M + H]⁺ = 499.2.

Example 306:9-((5-((3R,5R)-3-amino-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine

To a mixture of tert-butyl(tert-butoxycarbonyl)(9-((5-((3R,5R)-3-((tert-butoxycarbonyl)amino)-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-15methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-yl)carbamate (Intermediate306-9) (0.15 g, 0.19 mmol) in DCM (1 mL) was added HCl/Dioxane (10.0 mL,4M), and the resulting mixture was stirred at 25° C. for 4 hours. Themixture was concentrated in vacuo. The residue was purified by prep-HPLC(0.1% NH₄HCO₃ as additive as additive) to afford9-((5-((3R,5R)-3-amino-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine(Example 306). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 8.33 (s, 1H),8.14 (s, 1H), 7.67 (dd, J=2.0 Hz, 12.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H),7.30 (brs, 2H), 7.34-7.17 (m, 2H), 5.54 (s, 2H), 4.64-4.37 (m, 2H), 3.85(s, 3H), 3.18-3.03 (m, 3H), 2.92-2.77 (m, 2H), 2.48-2.32 (m, 1H),1.68-1.49 (m, 2H). LC-MS: [M+Na]⁺=481.2

Example 307-310 were prepared following procedures analogous to thepreparation of Example 306 and the corresponding intermediates.

Example # Structure HNMR & MS 307

¹HNMR (400 MHz, CD₃OD): δ 8.47 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H),7.79-7.75 (m, 2H), 7.24 (s, 1H), 7.16-7.12 (m, 2H), 6.14 (tt, J = 56.8Hz, 4.0 Hz, 1H), 5.61 (s, 2H), 3.08-3.06 (m, 2H), 2.83-2.80 (m, 1H),2.52-2.38 (m, 1H), 2.33-2.27 (m, 1H), 2.25-2.16 (m, 1H), 2.03-2.00 (m,1H), 1.95-1.91 (m, 1H), 1.09- 1.02 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H).LC-MS: [M + H]⁺ = 497.3 308

¹HNMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H),7.90-7.80 (m, 1H), 7.63-7.55 (m, 1H), 7.47 (q, J = 8.4 Hz, 1H), 7.33 (s,1H), 7.29 (brs, 2H), 5.54 (d, J = 2.0 Hz, 2H), 3.35-3.10 (m, 4H),3.09-2.95 (m, 4H), 2.87-2.75 (m, 2H), 2.35- 2.20 (m, 1H), 1.60-1.44 (m,2H). LC-MS: [M + H]⁺ = 481.2. 309

¹H NMR (400 MHz, CD₃OD): δ 8.51 (s, 1H), 8.21 (s, 1H), 8.20 (s, 1H),7.72 (ddd, J = 2.4 Hz, 8 Hz, 10 Hz, 1H), 7.54-7.47 (m, 1H), 7.32-7.22(m, 2H), 5.72-5.55 (m, 2H), 4.81-4.75 (m, 1H), 3.39-3.34 (m, 1H),3.28-3.25 (m, 1H), 3.17-3.07 (m, 2H), 2.91- 2.80(m, 1H), 2.36-2.24 (m,1H), 1.80-1.65(m, 1H). LC-MS: [M + H]⁺ = 455.2. 310

¹H NMR (400 MHz, CD₃OD): δ 8.55 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H),7.88-7.81 (m, 1H), 7.69-7.64 (m, 1H), 7.61 (s, 1H), 7.37-7.29 (m, 1H),5.80 (d, J = 15.6 Hz, 1H), 5.37 (d, J = 15.6 Hz, 1H), 3.28-3.24 (m, 2H),3.17-3.08 (m, 2H), 1.95-1.72 (m, 4H), 1.60-1.45 (m, 1H), 0.95-0.81 (m,2H), 0.61 (d, J = 6 Hz, 3H). LC-MS: [M + H]⁺ = 451.1.

Example 311-321 were prepared following procedures analogous to thepreparation of Example 47 and the corresponding intermediates.

Example # Structure ¹H NMR & MS 311

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.80(ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.64-7.57 (m, 1H), 7.47 (s, 1H), 7.31(dt, J = 10.4, 8.4 Hz, 1H), 6.21 (t, J = 75.3 Hz, 1H), 5.72-5.50 (m,2H), 3.99-3.85 (m, 2H), 3.54 (td, J = 5.8, 3.1 Hz, 1H), 3.25 (dt, J =6.7, 3.5 Hz, 1H), 3.00-2.84 (m, 2H), 1.76 (ddd, J = 15.8, 10.3, 5.7 Hz,3H), 1.60-1.47 (m, 1H). LC-MS: [M + H]⁺ = 517.2. 312

¹H NMR (CD₃OD): δ 8.62 (s, 1H), 8.21 (d, J = 36.6 Hz, 2H), 7.83 (ddd, J= 12.0, 7.8, 2.2 Hz, 1H), 7.72-7.51 (m, 2H), 7.32 (dt, J = 10.3, 8.5 _Hz, 1H), 5.79 (d, J = 15.6 Hz, 1H), 5.54 (d, J = 15.5 Hz, 1H), 3.72-3.45(m, 2H), 3.43-3.31 (m, 2H), 3.00-2.71 (m, 2H), 1.87-1.75 (m, 2H), 1.73-1.43 (m, 2H) LC-MS: [M + H]⁺ = 467.2. 313

¹H NMR (DMSO-d₆): δ 8.60 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 44.6, 5.3Hz, 2H), 7.89-7.14 (m, 4H), 5.95-5.36 (m, 3H), 3.70-3.36 (m, 5H), 3.24(s, 1H), 2.98-2.68 (m, 2H), 1.98-1.41 (m, 4H). LC-MS: [M + H]⁺ = 531.2.314

¹H NMR (400 MHz, CD₃OD): δ 8.58 (d, J = 17.0 Hz, 2H), 8.27 J = 17.6 Hz,2H), 7.84 (ddd, J = 11.9, 7.8, 2.1 Hz, 1H), 7.64 (dd, J = 11.4, 4.7 Hz,1H), 7.54 (s, 1H), 7.39-7.28 (m, 1H), 5.79-5.61 (m, 1H), 5.52 (t, J =20.8 Hz, 1H), 3.67-3.36 (m, 5H), 2.91 (d, J = 11.9 Hz, 1H), 2.24 (d, J =13.8 Hz, 1H), 1.91 (dd, J = 31.4, 16.3 Hz, 4H). LC-MS: [M + H]⁺ = 481.1.315

¹H NMR (400 MHz, CD₃OD): δ 8.47 (s, 1H), 8.27 (d, J = 3.0 Hz, 2H), 7.78(ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.58 (ddd, J = 10.4, 5.0, 2.4 Hz, 1H),7.46 (s, 1H), 7.30 (dt, J = 10.4, 8.4 Hz, 1H), 5.74 (q, J = 15.8 Hz,2H), 3.94 (d, J = 2.8 Hz, 1H), 3.25 (q, J = 2.8 Hz, 1H), 3.02 (d, J =11.7 Hz, 1H), 2.75 (t, J = 9.9 Hz, 1H), 2.57 (s, 3H), 1.93 (d, J = 3.4Hz, 1H), 1.79 (d, J = 9.2 Hz, 2H), 1.53 (d, J = 8.4 Hz, 1H). LC-MS: [M +H]⁺ = 494.1. 316

¹H NMR (CD₃OD): δ 8.59 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.70 (ddd, J= 12.1, 7.8, 2.2 Hz, 1H), 7.53-7.34 (m, 1H), 7.37-7.17 (m, 2H), 5.78-5.44 (m, 2H), 4.59 (qd, J = 8.4, 3.1 Hz, 1H), 3.82 (dd, J = 11.7, 3.4Hz, 1H), 3.66 (dd, J = 4.9, 3.2 Hz, 1H), 3.37 (dd, J = 11.9, 6.3 Hz,1H), 3.03 (dt, J = 11.8, 4.3 Hz, 1H), 1.92-1.61 (m, 4H). . LC- MS: [M +H]⁺ = 535.2. 317

¹H NMR (400 MHz, CD₃OD): δ 8.46 (s, 1H), 8.27 (d, J = 9.7 Hz, 2H), 7.79(ddd, J = 12.0, 7.8, 2.2 Hz, 1H), 7.63-7.54 (m, 1H), 7.48 (s, 1H), 7.30(dt, J = 10.4, 8.4 Hz, 1H), 5.79 (dd, J = 99.4, 15.7 Hz,2H), 4.62 (d, J= 2.5 Hz, 1H), 3.27 (d, J = 4.4 Hz, 1H), 3.20-3.09 (m, 3H), 2.95 (s,16H), 2.80 (s, 5H), 2.01-1.88 (m, 1H), 1.82 (td, J = 12.4, 3.8 Hz, 1H),1.71 (d, J = 11.9 Hz, 1H), 1.52-1.40(m, 1H).. LC-MS: [M + H]⁺ = 508.2318

¹H NMR (CD₃OD): δ 8.53 (d, J = 12.3 Hz, 1H), 8.25 (d, J = 10.5 Hz, 2H),7.84-7.70 (m, 1H), 7.67-7.53 (m, 1H), 7.46 (s, 1H), 7.30 (dt, J = 10.4,8.4 Hz, 1H), 5.86-5.50 (m, 2H), 4.03 (d, J = 2.7 Hz, 1H),3.48 (p, J =1.7 Hz, 1H), 3.13 (p, J = 1.6 Hz, 1H), 2.98-2.71 (m, 1H), 1.93 (s, 1H),1.81 (s, 2H), 1.53(s, 1H) LC-MS: [M + H]⁺ = 480.1. 319

¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H),7.89-7.71 (m, 1H), 7.56-7.49 (m, 1H), 7.49-7.39 (m, 1H), 7.29 (s, 2H),7.11 (br s, 1H), 5.59-5.33(m, 2H), 3.71 (br d, J = 2.9 Hz, 1H),3.60-3.50 (m, 1H), 3.05-2.90 (m, 2H), 2.00-1.85 (m, 1H), 1.85-1.70 m,1H),1.65-1.47 (m, 2H) LC-MS: [M + H]⁺ = 481.3 320

¹H NMR (CD₃OD): δ 8.54 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 4.6 Hz, 1H),8.17 (d, J = 3.7 Hz, 1H), 7.85- 7.60 (m, 1H), 7.58-7.39 (m, 1H),7.36-7.02 (m, 2H), 5.92-5.39 (m, 2H), 4.28-3.96 (m, 1H), 3.72-3.40 (m,2H), 3.20-2.90 (m, 1H), 2.69- 2.14 (m, 2H), 2.21-1.76 (m, 4H). LC-MS:[M + H]⁺ 321

¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H),7.98-7.85 (m, 1H), 7.70-7.60 (m, 1H), 7.57-7.45 (m, 1H), 7.42 (s, 1H),7.33 (brs, 2H), 5.54 (s, 2H), 3.85-3.50 (m, 3H), 3.49-3.37 (m, 1H),3.28-3.13 (m, 1H), 3.10- 2.70 (m, 5H), 1.85-1.48 (m, 4H). LC-MS: [M +H]⁺ = 493.2.

Example 322:(S)-3-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N-dimethylpropanamide

Example 322 was prepared following procedures analogous to thepreparation of Example 89 and the corresponding intermediate. ¹H NMR(400 MHz, CD₃OD) δ: 8.50 (s, 1H), 8.24 (d, J=10.8 Hz, 2H), 7.73 (ddd,J=12.3, 7.7, 2.3 Hz, 1H), 7.51 (t, J=5.7 Hz, 1H), 7.28 (d, J=8.5 Hz,2H), 5.85-5.51 (m, 2H), 3.10 (s, 3H), 2.99 (d, J=19.4 Hz, 4H), 2.93 (s,3H), 2.53 (t, J=8.1 Hz, 2H), 2.08-1.71 (m, 4H), 1.71-1.41 (in, 2H).LC-MS: [M+H]⁺=535.8, 536.8.

Example 323-325 were prepared following procedures analogous to thepreparation of Example 1 and the corresponding intermediates.

Example # Structure HNMR & MS 323

¹HMR (400 MHz, CD₃OD): δ d 8.51 (s, 2H), 8.44 (s, 1H), 8.27 (s, 1H),8.16 (s, 1H), 7.68 (ddd, J = 2.0, 8.0, 12.0 Hz, 1H), 7.53-7.47 (m, 1H),7.39-7.33 (m, 3H), 7.29-7.23 (m, 3H), 7.23-7.17 (m, 1H), 5.61 (s, 2H),4.20 (d, J = 9.6 Hz, 1H), 3.53-3.44 (m, 1H), 3.18-3.07 (m, 1H),2.94-2.85 (m, 1H), 2.39- 2.27 (m, 1H), 2.07-1.87 (m, 2H), 1.81-1.71 (m,1H). LC-MS: [M + H]⁺ = 513.2. 324

¹HNMR (400 MHz, CD₃OD): δ 8.57 (s, 1H), 8.23 (s, 0.4H), 8.22 (s, 1H),8.15 (s, 0.6H), 7.94-7.83 (m, 1H), 7.77-7.63 (m, 1.6H), 7.58 (s, 0.4H),7.40-7.28 (m, 1H), 7.52-7.46 (m, 1H), 5.34 (d, J = 15.6 Hz, 1H),3.86-3.75 (m, 1H), 3.60-3.51 (m, 1H), 3.48-3.41 (m, 0.6H), 3.36-3.34 (m,0.4H), 2.29-1.72 (m, 4H). LC- MS: [M + H]⁺ = 451.1. 325

¹H NMR (400 MHz, CD₃OD): δ 8.29 (d, J = 9.8 Hz, 2H), 8.13 (s, 1H), 7.72(ddd, J = 12.3, 7.8, 2.2 Hz, 1H), 7.60-7.54 (m, 1H), 7.49 (s, 1H), 7.27(dt, J = 10.4, 8.4 Hz, 1H), 5.42 (d, J = 2.0 Hz, 2H), 4.15- 3.93 (m,1H), 3.40 (qd, J = 13.1, 6.0 Hz, 2H), 2.53 _ 2.23 (m, 3H), 2.04-1.80 (m,1H) LC-MS: [M + H]⁺ = 450.9.Biological Assays

The compounds of the present invention may be evaluated for theirability to inhibit NSD2 using assays described below, as well as otherassays known in the art.

LC-MS/MS-Based NSD2 Enzymatic Assay

This assay employed LC-MS/MS technology to monitor the SAH productionfrom the NSD2 enzymatic reaction. The enzymatic reaction was performedin white proxiplate plus 384-well microplate (Perkin Elmer). Thereaction mixture (10 μL) were composed of 8 nM NSD2 [1-1365], 1 M SAM(USB, 10601) and 400 nM nucleosome (purified from mouse liver) inreaction buffer (20 mM Tris-HCl, pH at 8.0, 0.01% Tween 20, 10 mM MgCl2,50 mM NaCl, 1 mM DTT, 1 mM TCEP (pH7.5)). After 90 min incubation atroom temperature, 3 μL quenching solution containing 2.5% TFA with 320nM d4-SAH was added to stop the reaction.

For the inhibition assay, compound solutions were transferred into thewells by Mosquito™ (TTP LabTech). The inhibition assays were carried outby preincubating various concentrations of the inhibitor with 5 uLreaction mixture containing 16 nM NSD2 [1-1365] and 2 uM SAM (USB,10601) in reaction buffer. After 20 min preincubation, 5 uL solutioncontaining 800 nM nucleosome (purified from mouse liver) in reactionbuffer was added to initiate the reaction. The reaction was stopped by 3μL quenching solution containing 2.5% TFA with 320 nM d4-SAH after 90min.

The SAH production from the enzymatic assays were monitored by LC-MS/MSon an API 4000 triple quadrupole mass spec with Turbolon Spray (AppliedBiosystem) coupled with Prominenece UFLC(Shimazu). Liquid chromatographywas performed on a Chromolith FastGradient HPLC column (RP-18e, 25-2 mm,from Merck) at a flow rate of 0.8 ml/min. The column was connecteddirectly to the turbo ion electrospray operating in the positive-ionmode. Mobile phase A is 0.1% FA and 2% methanol in water and mobilephase B is 0.1% FA in ACN. Injection volume was 3 μl and the autosamplerwas kept at 4 degree. SAH and d4-SAH were simultaneously monitored. Datawere acquired and processed by Analyst software.

To quantify the formed SAH, d4-SAH was added as internal standard (IS).A series of SAH (Sigma, A9384) solution at varying concentration (1-500nM in reaction buffer) was mixed with quenching solution mentionedabove. Then LC-MS/MS was carried out on API 4000 LC/MS/MS system todetect both SAH and d4-SAH. The plot of SAH peak area/IS peak area vsSAH concentration was used to generate the normalization factor of SAH.The SAH production from real enzymatic reaction was derived from thestandard curve of SAH. The down-limit of our system for the detection ofSAH is around 1-2 nM, and the linear range can reach up to 500 nM.

In one embodiment, the compounds of the invention has an NSD2 IC₅₀<0.01μM. In particular embodiments, the compounds of the invention has anNSD2 IC₅₀ between 0.001 μM and 0.01 μM, as exemplified in Table 2(“+++”). In another embodiment, the compounds of the invention has anNSD2 IC₅₀<1 μM. In particular embodiments, the compounds of theinvention has an NSD2 IC₅₀ between 0.01 and 1 μM., as exemplified inTable 2 (“++”). In yet another embodiment, the compounds of theinvention has an NSD2 IC₅₀>1 μM, as exemplified in Table 2 (“+”).

H3K36Me2 Cellular FRET Assay in KMS11-Par Line

Fluorescence Resonance Energy Transfer (FRET) assay was used to test theability of candidate compound to reduce cellular H3K36me2 level inmultiple myeloma cell line KMS11 (t(4;14)+) (Horizon Discovery Ltd.).Cells are maintained in RPM11640 media with 12.5% FBS and 50 U/mlPenicillin-Streptomycin. For assay compound treatment, single cellsuspension was prepared in Opti-MEM supplemented with B-27 and N2supplement (Invitrogen 11058-021, 17504-044, 17502-048). One day priorto cell treatment, 5,000 KMS11 cells were seeded into PDL coated TCplate (PerkinElmer #6007718) at the final volume of 30 μL/well.

Cells were treated with tested compounds at the desired concentrationfor 48 hours. Crude histone lysate was extracted by 0.4M HCl followingneutralization by 0.5M Sodium phosphate, dibasic (Na2HPO4), pH ˜12.5.Histone extract was incubated with Eu labeled anti-H3K36me2 antibody(abcam #ab ab9049) and d2 labeled anti-H3 antibody (abcam #ab1791) for 1hour at room temperature. A Eu labeled anti-H3 antibody (CISBIO#64CUS000) was used for loading control. The abundancy of H3K36me2 ortotal H3 was measured by fluorescence signal on Perkin Elmer Envisonmachine.

H3K36Me2 Cellular ELISA Assay in CGTH-W-1 Line

An ELISA (enzyme-linked immunosorbent assay) based assay was used totest the ability of candidate compound to reduce cellular H3K36me2 levelin thyroid carcinoma cell line CGTH-W-1, carrying NSD2 E1099K gain offunction mutation. CGTH-W-1 (DSMZ) cells are maintained in RPM11640media with 10% FBS and 50 U/ml Penicillin-Streptomycin. For assaycompound treatment, single cell suspension was prepared in Opti-MEMsupplemented with B-27 and N2 supplement (Invitrogen 11058-021,17504-044, 17502-048) for ELISA and in maintenance media for cellTiterGlo (CTG) viability assay. One day prior to cell treatment, 500 CGTH-W-1cells were seeded into 384-well Greiner CellStar TC plate (Greiner#781086) at the final volume of 30 μL/well.

Cells were treated with tested compounds at the desired concentrationfor 72 hours. Crude histone lysate was extracted by 0.4M HCl followingneutralization by 0.5M Sodium phosphate, dibasic (Na₂HPO₄), pH ˜12.5.Equal amount of histone lysate was loaded to Corning 384-well highbiding plate (Corning #3577, black) for H3K36me2 and to Thermo 384-wellhigh binding Nunc plate (Thermo #460372, white) for total H3 as loadingcontrol.

Histone bound plates were washed and blocked with 5% BSA. H3K36me2 andtotal H3 was detected by primary antibodies (H3K36me2 Abcam, #ab9049;total H3 Cell Signaling, #4499L) and further revealed by horseradishperoxidase (HRP) conjugated secondary antibody and ECL substrate. Theabundance of H3K36me2 and total H3 was measured by Chemiluminesce on aplate reader. Cell viability was monitored on a parallel seeded platewith CellTiter-Glo reagent (Promega #G7573).

H3K36Me2 Cellular ELISA Assay in KMS11-Par Line

An ELISA (enzyme-linked immunosorbent assay) based assay was used totest the ability of candidate compound to reduce cellular H3K36me2 levelin multiple myeloma cell line KMS11 (t(4;14)+). KMS11 (Horizon DiscoveryLtd.) cells are maintained in RPM11640 media with 12.5% FBS and 50 U/mlPenicillin-Streptomycin. For assay compound treatment, single cellsuspension was prepared in Opti-MEM supplemented with B-27 and N2supplement (Invitrogen 11058-021, 17504-044, 17502-048) for ELISA and inmaintenance media for cellTiter Glo (CTG) viability assay. One day priorto cell treatment, 1,250 KMS11 cells were seeded into 384-well GreinerCellStar TC plate (Greiner #781086) at the final volume of 30 μL/well.

Cells were treated with tested compounds at the desired concentrationfor 72 hours. Crude histone lysate was extracted by 0.4M HCl followingneutralization by 0.5M Sodium phosphate, dibasic (Na₂HPO₄), pH ˜12.5.Equal amount of histone lysate was loaded to Corning 384-well highbiding plate (Corning #3577, black) for H3K36m2 and to Thermo 384-wellhigh binding Nunc plate (Thermo #460372, white) for total H3.

Histone bound plates were washed and blocked with 5% BSA. H3K36me2 andtotal H3 was detected by primary antibodies (H3K36me2 Abcam, #ab9049;total H3 Cell Signaling, #4499L) and further revealed by horseradishperoxidase (HRP) conjugated secondary antibody and ECL substrate. Theabundance of H3K36me2 and total H3 was measured by Chemiluminesce on aplate reader. Cell viability was monitored on a parallel seeded platewith CellTiter-Glo reagent (Promega #G7573).

H3K36Me2 Cellular ELISA Assay in CGTH-W-1 Line

An ELISA (enzyme-linked immunosorbent assay) based assay was used totest the ability of candidate compound to reduce cellular H3K36me2 levelin thyroid carcinoma cell line CGTH-W-1, carrying NSD2 E1099K gain offunction mutation. CGTH-W-1 (DSMZ) cells are maintained in RPM11640media with 10% FBS and 50 U/ml Penicillin-Streptomycin. For assaycompound treatment, single cell suspension was prepared in Opti-MEMsupplemented with B-27 and N2 supplement (Invitrogen 11058-021,17504-044, 17502-048) for ELISA and in maintenance media for cellTiterGlo (CTG) viability assay. One day prior to cell treatment, 500 CGTH-W-1cells were seeded into 384-well Greiner CellStar TC plate (Greiner#781086) at the final volume of 30 μL/well.

Cells were treated with tested compounds at the desired concentrationfor 72 hours. Crude histone lysate was extracted by 0.4M HCl followingneutralization by 0.5M Sodium phosphate, dibasic (Na₂HPO₄), pH ˜12.5.Equal amount of histone lysate was loaded to Corning 384-well highbiding plate (Corning #3577, black) for H3K36me2 and to Thermo 384-wellhigh binding Nunc plate (Thermo #460372, white) for total H3 as loadingcontrol.

Histone bound plates were washed and blocked with 5% BSA. H3K36me2 andtotal H3 was detected by primary antibodies (H3K36me2 Abcam, #ab9049;total H3 Cell Signaling, #4499L) and further revealed by horseradishperoxidase (HRP) conjugated secondary antibody and ECL substrate. Theabundance of H3K36me2 and total H3 was measured by Chemiluminesce on aplate reader. Cell viability was monitored on a parallel seeded platewith CellTiter-Glo reagent (Promega #G7573).

The NSD2 biochemical activity and H3K36me2 cellular activity of thecompounds of the present invention in different assay formats and celllines are summarized in Table 2.

TABLE 2 H3K36me2 H3K36me H3K36me2 FRET in 2 ELISA in ELISA in NSD2 ExKMS11-Par CGTH-W- KMS11-Par IC₅₀ No. (μM) 1 (μM) (μM) (μm) 1(R)-9-((5-(3-aminopiperidin-1-yl)- 3.03 0.75 4.09 ++ 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 29-((5-((3S,4R)-3-amino-4- 11.07 n/a n/a ++ fluoropiperidin-1-yl)-2-(2-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 3(3S,4R)-3-amino-1-(4-((6-amino- n/a 8.25 33.3 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-4-ol 4 (R)-9-((5-(3-aminopiperidin-1-yl)- 4.12 n/a n/a ++2-(3-fluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 59-((5-((3S,4R)-3-amino-4- 6.46 1.77 n/a ++fluoropiperidin-1-yl)-2-(3-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 6 (R)-9-((5-(3-aminopiperidin-1-yl)- 10.0n/a n/a ++ 2-(2-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 7 (R)-4-(4-((6-amino-9H-purin-9- 15.1 n/an/a ++ yl)methyl)-5-(3-aminopiperidin-1-yl)pyridin-2-yl)-2-chlorobenzonitrile 8 9-((5-((3S,4R)-3-amino-4- 5.26n/a n/a ++ fluoropiperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 94-(5-((2S,3R)-3-amino-2- 9.90 n/a n/a ++ (methoxymetpiperidin-1-yl)-4-((6-amino-9H-purin-9- yl)methyl)pyridin-2-yl)-2- fluorobenzonitrile 109-((5-((3S,4R)-3-amino-4- 7.63 n/a n/a ++fluoropiperidin-1-yl)-2-(2-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 11 (R)-9-((5-(3-aminopiperidin-1- 11.2 n/an/a ++ yl)-2-(4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 129-((5-((3S,4R)-3-amino-4- 12.2 n/a n/a ++ fluoropiperidin-1-yl)-2-(3-chlorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 134-(5-((3S,4R)-3-amino-4- 20.7 n/a n/a ++fluoropiperidin-1-yl)-4-((6-amino- 9H-purin-9-yl)methyl)pyridin-2-yl)-2-fluorobenzonitrile 14 9-((5-((3S,4R)-3-amino-4- n/a n/a n/a ++fluoropiperidin-1-yl)-2-(2,3- dihydrobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 15 9-((5-(3-amino-4- 18.7 n/a n/a ++methoxypiperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 16 (R)-9-((5-(5-amino-3,3- n/a n/a n/a ++difluoropiperidin-1-yl)-2-(3-fluoro- 4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 17 9-((5-(3-amino-4,4- 154 n/a n/a +difluoropiperidin-1-yl)-2-(3- fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 18 3-amino-1-(4-((6-amino-9H-purin- n/a n/a n/a +9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidine-4-carbonitrile 19 (R)-1-((5-(3-aminopiperidin-1-yl)- 3.90n/a n/a ++ 2-(3-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-7-chloro-1H- imidazo[4,5-c]pyridin-4-amine 20(R)-9-((5-(3-amino-3- 2.95 n/a n/a ++ methylpiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 21(R)-1-((5-(3-aminopiperidin-1-yl)- 20.8 n/a n/a ++ 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 22(R)-9-((5-(3-amino-3- 0.214 n/a n/a +++ (cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin- 4-yl)methyl)-9H-purin-6-amine 23(R)-9-((5-(3-amino-3- 0.160 n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 24 (R)-9-((5-(3-amino-3- 0.451 n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 25 (R)-9-((5-(3-amino-3- 0.995 n/a n/a +++(isopropoxymethyl)piperidin-1-yl)- 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 26(R)-9-((5-(3-amino-3- 0.248 n/a 0.375 +++(methoxymethyl)piperidin-1-yl)-2- (5-chloro-2-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 27 (R)-9-((5-(3-amino-3- 0.501 n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (3-chlorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 28 (R)-9-((5-(3-amino-3- n/a n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (3-chloro-4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 29 (R)-9-((5-(3-amino-3- 0.225 n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (2,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 30 (R)-9-((5-(3-amino-3- 0.569 0.659 2.03+++ (cyclobutoxymethyl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 31 (R)-9-((5-(3-amino-3- n/a n/a n/a +++(cyclopropoxymethyl)piperidin-1- yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 32(R)-9-((5-(3-amino-3- 0.270 0.196 0.728 +++(cyclobutoxymethyl)piperidin-1- yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 33(R)-9-((5-(3-amino-3- 1.03 n/a n/a +++ (methoxymethyl)piperidin-1-yl)-2-(2-fluoro-4- methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 34(R)-9-((5-(3-amino-3- 1.03 n/a n/a +++(isopropoxymethyl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 35 (R)-9-((5-(3-amino-3- 0.610 n/a n/a +++(cyclobutoxymethyl)piperidin-1- yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 36 (R)-9-((5-(3-amino-3- 0.416 n/a n/a ++(cyclobutoxymethyl)piperidin-1- yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 37 (R)-9-((5-(3-amino-3- 0.614 n/a 1.40 ++(isopropoxymethyl)piperidin-1-yl)- 2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 38 (R)-9-((5-(3-amino-3- 0.721 n/a n/a ++(methoxymethyl)piperidin-1-yl)-2- (3-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 39 (R)-9-((5-(3-amino-3-((2,2,2- 2.56 n/an/a ++ trifluoroethoxy)methyl)piperidin- 1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 40(R)-9-((5-(3-amino-3- 0.770 n/a n/a ++((difluoromethoxy)methyl)piperidin- 1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 41 (R)-9-((5-(3-amino-3- 1.09 2.31 ++((difluoromethoxy)methyl)piperidin- 1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 42(R)-9-((5-(3-amino-3- 1.23 0.789 10.7 ++((difluoromethoxy)methyl)piperidin- 1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 43(R)-9-((5-(3-amino-3-((2,2,2- 1.24 n/a n/a ++trifluoroethoxy)methyl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 44 (R)-9-((5-(3-amino-3- 1.62 n/a n/a ++((difluoromethoxy)methyl)piperidin- 1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 45 (R)-9-((5-(3-amino-3-((2,2,2- 0.705 n/an/a ++ trifluoroethoxy)methyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 46(R)-1-((5-(3-amino-3- 0.315 n/a n/a +++(methoxymethyl)piperidin-1-yl)-2- (3-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 47(S)-9-((5-(3-amino-3-(2,2- 1.18 0.377 1.54 ++difluoroethyl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 48 (S)-1-((5-(3-amino-3-(thiazol-2- n/a n/a0.464 +++ ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 49(S)-1-((5-(3-amino-3-((1-methyl- n/a n/a 12.7 +++1H-pyrazol-3-yl)methyl)piperidin- 1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 50(S)-1-((5-(3-amino-3-(pyridin-2- n/a n/a 0.895 +++ylmethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 51(S)-1-((5-(3-amino-3-(pyridin-2- n/a n/a 1.53 +++ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 52(S)-9-((5-(3-amino-3-(oxazol-2- 1.20 0.541 1.32 +++ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 53 (S)-9-((5-(3-amino-3-(thiazol-2- 0.327n/a n/a +++ ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 54 (S)-9-((5-(3-amino-3-(pyridin-2- 0.450n/a 0.780 +++ ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 55 (S)-9-((5-(3-amino-3-((6- n/a n/a 0.910+++ methylpyridin-2-yl)methyl)piperidin- 1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 56(S)-9-((5-(3-amino-3-((1-methyl- n/a 0.273 0.234 +++1H-pyrazol-3-yl)methyl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 57(S)-1-((5-(3-amino-3-(thiazol-2- n/a n/a 0.610 +++ylmethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 58(S)-2-(3-amino-1-(4-((6-amino- 2.64 n/a n/a +++9H-purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)piperidin-3-yl)acetic acid 59 (S)-2-(3-amino-1-(4-((4-amino- 33.3 n/an/a +++ 1H-imidazo[4,5-c]pyridin-1- yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-N,N- dimethylacetamide 609-((5-(3-amino-3-(2- n/a n/a n/a ++ methoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 61(S)-9-((5-(3-amino-3-(2,2- 1.42 0.643 n/a ++difluoroethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 62 (S)-2-(3-amino-1-(4-((6-amino- n/a n/an/a ++ 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)acetamide 63 (S)-1-((5-(3-amino-3-(oxazol-2- n/a n/a7.91 ++ ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 64 N-(4-(5-(3-amino-3-(2,2-n/a n/a 7.00 ++ difluoroethyl)piperidin-1-yl)-4-((6- amino-9H-purin-9-yl)methyl)pyridin-2-yl)phenyl)-3- bromopropanamide 659-((5-((S)-3-amino-3-((R)-1- n/a n/a 1.13 ++(pyridin-2-yl)ethyl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 66 2-(3-amino-1-(4-((6-amino-9H- 118 n/a n/a++ purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)piperidin-3-yl)-N- methylacetamide 67 2-(3-amino-1-(4-((4-amino-7-4.25 n/a n/a ++ chloro-1H-imidazo[4,5-c]pyridin- 1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-N- methylacetamide 682-(3-amino-1-(4-((4-amino-7- n/a n/a n/a ++chloro-1H-imidazo[4,5-c]pyridin- 1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-N,N- dimethylacetamide 699-((5-(3-amino-3-((6-fluoropyridin- n/a n/a 1.15 ++2-yl)methyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 70 (S)-2-(3-amino-1-(4-((6-amino- 9.44 n/an/a ++ 9H-purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N- dimethylacetamide 71 (S)-9-((5-(3-amino-3-(2,2-0.849 n/a n/a ++ difluoroethyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 722-(3-amino-1-(4-((4-amino-1H- 250 n/a n/a ++ imidazo[4,5-c]pyridin-1-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3- yl)piperidin-3-yl)-N-methylacetamide 73 methyl (S)-2-(3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)piperidin-3-yl)acetate 74 (S)-9-((5-(3-amino-3-(pyrazin-2- n/a n/a4.22 ++ ylmethyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 75 N-(4-(5-(3-amino-3-(2,2- n/a n/a n/a ++difluoroethyl)piperidin-1-yl)-4-((6- amino-9H-purin-9-yl)methyl)pyridin-2-yl)benzyl)-2- chloroacetamide 76N-(4-(5-(3-amino-3-(2,2- n/a n/a 2.12 ++difluoroethyl)piperidin-1-yl)-4-((6- amino-9H-purin-9-yl)methyl)pyridin-2- yl)phenyl)acrylamide 772-(3-amino-1-(4-((6-amino-9H- n/a n/a n/a + purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)acetonitrile 78(R)-3-amino-1-(4-((6-amino-9H- n/a 0.012 0.078 +++purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)-N-methylpiperidine-3-carboxamide 79 methyl (R)-3-amino-1-(4-((6- 0.473 n/an/a +++ amino-9H-purin-9-yl)methyl)-6-(3- fluorophenyl)pyridin-3-yl)piperidine-3-carboxylate 80 (R)-3-amino-1-(4-((6-amino-9H- 4.95 n/an/a +++ purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)-N,N- dimethylpiperidine-3- carboxamide 81isopropyl (R)-3-amino-1-(4-((6- 0.115 n/a n/a +++amino-9H-purin-9-yl)methyl)-6-(3- fluoro-4-methoxyphenyl)pyridin-3-yl)piperidine-3-carboxylate 82 (R)-3-amino-1-(4-((6-amino-9H- n/a n/an/a ++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-3-carboxamide 83 tert-butyl(R)-3-amino-1-(4-((6- 0.956 n/a n/a ++ amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3- yl)piperidine-3-carboxylate 84(R)-(3-amino-1-(4-((6-amino-9H- n/a n/a n/a ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(pyrrolidin-1- yl)methanone 853-amino-1-(4-((6-amino-9H-purin- n/a 2.08 6.49 ++ 9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-N- (tetrahydrofuran-3-yl)piperidine-3-carboxamide 86 (3-amino-1-(4-((6-amino-9H- n/a 8.69 33.3 ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(piperidin-1- yl)methanone 87(3-amino-1-(4-((6-amino-9H- n/a 1.60 6.42 ++ purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)(2-methylpiperidin-1-yl)methanone 88 (3-amino-1-(4-((6-amino-9H- n/a n/an/a ++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(2- methylpyrrolidin-1-yl)methanone 891-(3-amino-1-(4-((6-amino-9H- n/a 0.245 0.684 ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,3- dimethylbutan-1-one 90(R)-1-((R)-3-amino-1-(4-((6- n/a 0.239 0.432 +++amino-9H-purin-9-yl)methyl)-6-(3- fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-ol 91 9-((5-((R)-3-amino-3-((S)- n/a 0.1210.890 +++ fluoro(pyridin-2- yl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 92(S)-1-((R)-3-amino-1-(4-((6- n/a 2.11 4.89 +++amino-9H-purin-9-yl)methyl)-6-(3- fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-ol 93 9-((5-((R)-3-amino-3-((S)-1- 1.39 3.213.97 ++ methoxyethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 949-((5-((R)-3-amino-3-((R)-1- 3.04 1.09 1.20 ++methoxyethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 95 9-((5-((R)-3-amino-3-((S)-1- 1.82 1.653.03 ++ methoxyethyl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 96 (E)-1-(3-amino-1-(4-((6-amino- 2.40 n/an/a ++ 9H-purin-9-yl)methyl)-6-(3-fluoro- 4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-one O- methyl oxime 979-((5-((R)-3-amino-3-((R)-1- 1.50 1.16 1.24 ++methoxyethyl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 98 (S)-1-((R)-3-amino-1-(4-((6- n/a 1.506.26 ++ amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylpropan- 1-ol 99 9-((5-(3-amino-3-((R)-1- n/an/a 21.0 ++ ethoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 100(3-amino-1-(4-((6-amino-9H- n/a n/a n/a +++ purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3- yl)(cyclopentyl)methanone 101(S)-1-((R)-3-amino-1-(4-((6- n/a 0.040 0.034 +++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylbutan- 1-one 102 (R)-1-((R)-3-amino-1-(4-((6-n/a 0.060 0.252 ++ amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2-methylbutan- 1-one103 1-(3-amino-1-(4-((6-amino-9H- n/a 0.138 0.379 ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2- cyclopropylpropan-1-one 104(R)-1-(3-amino-1-(4-((6-amino- n/a 0.026 0.060 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylpropan- 1-one 105 (3-amino-1-(4-((6-amino-9H-n/a 0.067 0.140 ++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3- yl)(cyclobutyl)methanone 106 (3-amino-1-(4-((6-amino-9H-n/a 0.501 1.43 ++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(3- methoxycyclopentyl)methanone 107(3-amino-1-(4-((6-amino-9H- n/a 0.446 3.02 ++ purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)(1-methylcyclopropyl)methanone 108 (3-amino-1-(4-((6-amino-9H- n/a 0.7721.96 ++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(tetrahydro-2H- pyran-4-yl)methanone 109(R)-1-(3-amino-1-(4-((6-amino- n/a 2.092 2.729 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- dimethylpropan-1-one 110(3-amino-1-(4-((6-amino-9H- n/a 1.359 6.340 ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(1-methyl-1H- pyrazol-3-yl)methanone 111(3-amino-1-(4-((6-amino-9H- n/a n/a n/a + purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)(tetrahydrofuran-3-yl)methanone 112 (3-amino-1-(4-((6-amino-9H- n/a n/a n/a +purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)(3-methyloxetan- 3-yl)methanone 113(R)-1-((R)-3-amino-1-(4-((6- n/a 0.145 0.753 ++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 114(S)-1-((R)-3-amino-1-(4-((6- n/a 0.443 1.94 ++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 115(R)-1-((R)-3-amino-1-(4-((6- n/a 0.088 0.927 +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2-methylphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 116(S)-1-((R)-3-amino-1-(4-((6- n/a 0.168 1.35 +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-3-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 117(R)-1-((R)-3-amino-1-(4-((6- n/a 0.067 1.32 +++amino-9H-purin-9-yl)methyl)-6- (4,5-difluoro-2- methylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 118(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a +++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)-5-methoxypyridin-3-yl)piperidin-3- yl)-2,2-difluoroethan-1-ol 119(R)-1-((R)-3-amino-1-(4-((6- n/a 0.228 1.49 +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-3-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 120(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 121(R)-1-((R)-3-amino-1-(4-((6- n/a 0.683 2.61 +++amino-9H-purin-9-yl)methyl)-6-(3- chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 122(R)-1-((R)-3-amino-1-(4-((6- n/a 0.496 1.83 +++amino-9H-purin-9-yl)methyl)-6-(3- chloro-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 123(R)-1-((R)-3-amino-1-(4-((6- n/a 1.49 7.85 +++amino-9H-purin-9-yl)methyl)-6-(6- fluoro-1-methyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 124(R)-1-((R)-3-amino-1-(4-((6- n/a 0.159 0.848 +++amino-9H-purin-9-yl)methyl)-6-(4- chloro-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 125(S)-1-((R)-3-amino-1-(4-((6- n/a 0.775 3.95 +++amino-9H-purin-9-yl)methyl)-6- (3-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 126(R)-1-((R)-3-amino-1-(4-((6- n/a 0.469 1.11 +++amino-9H-purin-9-yl)methyl)-6- (2,4-dimethylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 127(S)-1-((R)-3-amino-1-(4-((6- n/a 0.262 0.901 +++amino-9H-purin-9-yl)methyl)-6-(3- fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 128(S)-1-((R)-3-amino-1-(4-((6- n/a 0.060 0.693 +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-2,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 129(R)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-5-fluoro-2-methylphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 130(R)-1-((R)-3-amino-1-(4-((6- n/a 0.321 3.52 +++amino-9H-purin-9-yl)methyl)-6- cyclohexylpyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 131 (R)-1-((R)-3-amino-1-(4-((6- n/a 0.1420.887 +++ amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3- yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 132 (R)-1-((R)-3-amino-1-(4-((6- n/a 0.264 1.23 +++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 133(R)-1-((R)-3-amino-1-(4-((6- n/a 0.177 1.61 ++amino-9H-purin-9-yl)methyl)-6-(4- chloro-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 134(R)-1-((R)-3-amino-1-(4-((6- n/a 0.601 0.830 ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 135(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-5- fluoro-6-(2-fluoro-4-methoxyphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 136(R)-1-((R)-3-amino-1-(4-((6- n/a n/a 8.80 ++amino-9H-purin-9-yl)methyl)-6- (1,6-dimethyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 137(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 138(R)-1-((R)-3-amino-1-(4-((6- n/a 0.132 1.57 ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-2-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 139(S)-1-((R)-3-amino-1-(4-((6- n/a 0.669 2.84 ++amino-9H-purin-9-yl)methyl)-6-(3- chloro-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 140(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethyl)-2-methylphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 141(R)-1-((R)-3-amino-1-(4-((6- n/a 1.15 7.70 ++amino-9H-purin-9-yl)methyl)-6-(2- fluoro-4-(trifluoromethyl)phenyl)pyridin-3- yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 142 (S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6- (2,4-difluorophenyl)-5-fluoropyridin-3-yl)piperidin-3-yl)- 2,2-difluoroethan-1-ol 143(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6-(6- fluoro-1-methyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 1444-(5-((R)-3-amino-3-((S)-2,2- n/a 2.58 10.4 ++difluoro-1-hydroxyethyl)piperidin- 1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)-2,5- difluorophenol 145(S)-1-((R)-3-amino-1-(4-((6- n/a 0.990 8.11 ++amino-9H-purin-9-yl)methyl)-6- cyclohexylpyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 146 (S)-1-((R)-3-amino-1-(4-((6- n/a 0.7235.04 ++ amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 147(R)-1-((R)-3-amino-1-(4-((6- n/a 0.044 2.49 ++amino-9H-purin-9-yl)methyl)-6- (2,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 148(S)-1-((R)-3-amino-1-(4-((6- n/a 0.671 2.16 ++amino-9H-purin-9-yl)methyl)-6-(4- chloro-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 149(S)-1-((R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6- (2,5-difluoro-4-methoxyphenyl)-5-fluoropyridin-3-yl)piperidin-3-yl)- 2,2-difluoroethan-1-ol 150(R)-1-((R)-3-amino-1-(4-((6- n/a 0.307 1.67 ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-2,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 151(S)-1-((R)-3-amino-1-(4-((6- n/a 0.8415 4.19 ++amino-9H-purin-9-yl)methyl)-6- (2,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 152(S)-1-((R)-3-amino-1-(4-((6- n/a 0.0687 1.77 ++amino-9H-purin-9-yl)methyl)-6-(4- chloro-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 153(S)-1-((R)-3-amino-1-(4-((6- n/a 0.217 5.08 ++amino-9H-purin-9-yl)methyl)-6-(4- (difluoromethoxy)-2-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 154(R)-1-((R)-3-amino-1-(4-((6- n/a 2.93 9.11 ++amino-9H-purin-9-yl)methyl)-6-(3- (difluoromethyl)-2,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 155(R)-1-((R)-3-amino-1-(4-((6- n/a 1.17 16.4 ++amino-9H-purin-9-yl)methyl)-5′- fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 156(R)-1-((R)-3-amino-1-(4-((6- n/a 0.041 0.574 +++amino-9H-purin-9-yl)methyl)-6- (2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 157(S)-1-((R)-3-amino-1-(4-((6- n/a 0.385 1.31 +++amino-9H-purin-9-yl)methyl)-6- (2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 158(R)-1-((R)-3-amino-1-(4-((6- n/a 0.100 0.802 +++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or159 (S)-1-((R)-3-amino-1-(4-((6- n/a 0.140 1.13 +++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4-fluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 160(R)-1-((R)-3-amino-1-(4-((6- n/a 0.035 0.434 +++amino-9H-purin-9-yl)methyl)-6- (2,5-difluoro-4- methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 161(S)-1-((R)-3-amino-1-(4-((6- n/a 0.073 0.502 +++amino-9H-purin-9-yl)methyl)-6- (2,5-difluoro-4- methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 162(R)-1-((R)-3-amino-1-(4-((6- n/a 0.086 0.440 +++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4-methoxyphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or163 (S)-1-((R)-3-amino-1-(4-((6- n/a 0.204 1.85 +++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4-methoxyphenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 164(R)-1-((R)-3-amino-1-(4-((6- n/a 0.130 1.06 +++amino-9H-purin-9-yl)methyl)-6- (3,5-difluoro-4- methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 165(S)-1-((R)-3-amino-1-(4-((6- n/a 0.218 1.08 +++amino-9H-purin-9-yl)methyl)-6- (3,5-difluoro-4- methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 166(S)-1-((R)-3-amino-1-(4-((6- n/a 0.432 8.51 +++amino-9H-purin-9-yl)methyl)-6-(4- methoxy-2-(trifluoromethyl)phenyl)pyridin-3- yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or 167 (R)-1-((R)-3-amino-1-(4-((6- n/a 0.559 6.12++ amino-9H-purin-9-yl)methyl)-6-(4- methoxy-2-(trifluoromethyl)phenyl)pyridin-3- yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 168 (S)-1-((R)-3-amino-1-(4-((6- n/a 0.997 4.78 ++amino-9H-purin-9-yl)methyl)-6-(2- chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 169(R)-1-((R)-3-amino-1-(4-((6- n/a 0.426 2.99 ++amino-9H-purin-9-yl)methyl)-6-(2- chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 170(R)-1-((R)-3-amino-1-(4-((6- n/a 0.161 1.47 ++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or171 (S)-1-((R)-3-amino-1-(4-((6- n/a 0.886 5.52 ++amino-9H-purin-9-yl)methyl)-6-(2- (difluoromethyl)-4,5-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 172(R)-1-((R)-3-amino-1-(4-((6- n/a 1.20 8.93 ++amino-9H-purin-9-yl)methyl)-6- (2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 173(S)-1-((R)-3-amino-1-(4-((6- n/a 1.04 12.8 ++amino-9H-purin-9-yl)methyl)-6-(4- fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 174(R)-1-((R)-3-amino-1-(4-((6- n/a 1.16 10.6 ++amino-9H-purin-9-yl)methyl)-6-(4- fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 175(S)-1-((R)-3-amino-1-(4-((6- n/a 0.534 11.3 ++amino-9H-purin-9-yl)methyl)-6′- chloro-g-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol; or 176(R)-1-((R)-3-amino-1-(4-((6- n/a 0.953 8.97 ++amino-9H-purin-9-yl)methyl)-6′- chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2- difluoroethan-1-ol 177 9-((5-(3-amino-3-(6- n/an/a 0.407 +++ methylpyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 178(R)-9-((5-(3-amino-3-(6- n/a 0.230 n/a +++methoxypyridin-2-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 179 9-((5-(3-amino-3-(6-chloropyridin- n/a1.42 n/a ++ 2-yl)piperidin-1-yl)-2-(1,3- dihydroisobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6- amine 180 (R)-9-((5-(3-amino-3-(6-n/a 1.459 5.49 ++ chloropyridin-2-yl)piperidin-1-yl)-5′-chloro-6′-fluoro-[2,3′-bipyridin]- 4-yl)methyl)-9H-purin-6-amine 181(R)-9-((5-(3-amino-3-(6- n/a 1.56 1.98 ++chloropyridin-2-yl)piperidin-1-yl)- 2-(2-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 182(R)-9-((5-(3-amino-3-(6- n/a 0.0975 0.142 +++cyclopropylpyridin-2-yl)piperidin- 1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 183 9-((5-((R)-3-amino-3-(6-((S)-1- n/a0.159 0.455 ++ fluoroethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 1849-((5-(3-amino-3-(6-chloropyridin- n/a 0.592 n/a ++2-yl)piperidin-1-yl)-2-(4- (difluoromethoxy)phenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 185 (R)-9-((5-(3-amino-3-(6- n/a n/a n/a++ chloropyridin-2-yl)piperidin-1-yl)- 2-(2,3-dihydrobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6- amine 1869-((5-(3-amino-3-(6-chloropyridin- n/a 0.967 n/a ++2-yl)piperidin-1-yl)-2- (benzo[d][1,3]dioxo1-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 187 (R)-9-((5-(3-amino-3-(6- n/a 0.3830.815 ++ chloropyridin-2-yl)piperidin-1-yl)- 2-(2,5-difluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 188(R)-9-((5-(3-amino-3-(6-chloro-5- n/a 1.01 1.91 +++fluoropyridin-2-yl)piperidin-1-yl)- 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 1899-((5-(3-amino-3-(5-fluoropyridin- n/a n/a n/a ++2-yl)piperidin-1-yl)-2-(4- fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 190 (R)-9-((5-(3-amino-3-(5-fluoro-6- n/a 0.258 0.687+++ methylpyridin-2-yl)piperidin-1-yl)- 2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 191 (R)-9-((5-(3-amino-3-(6- n/a 1.38 4.56++ chloropyridin-2-yl)piperidin-1-yl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]- 4-yl)methyl)-9H-purin-6-amine 192(R)-9-((5-(3-amino-3-(6-chloro-3- n/a 0.731 2.18 ++fluoropyridin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 193 9-((5-(3-amino-3-(5-fluoro-6- n/a 0.8761.85 ++ (fluoromethyl)pyridin-2- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 194(R)-9-((5-(3-amino-3-(6- n/a 0.805 3.28 ++chloropyridin-2-yl)piperidin-1-yl)- 6′-chloro-5′-methoxy-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6- amine 1956-(3-amino-1-(4-((6-amino-9H- n/a 4.92 n/a ++ purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)picolinamide 196(R)-9-((5-(3-amino-3-(6- n/a 0.637 2.69 ++chloropyridin-2-yl)piperidin-1-yl)- 5′-fluoro-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 197 (R)-9-((5-(3-amino-3-(6-(1,1-difluoroethyl)pyridin-2- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 198(R)-9-((5-(3-amino-3-(pyridin-2- n/a 0.0177 0.041 +++yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 199 (R)-9-((5-(3-amino-3-(3- n/a n/a 0.846+++ fluoropyridin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 200 (R)-9-((5-(3-amino-3-(6- n/a 0.18 0.33+++ chloropyridin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 201 (R)-9-((5-(3-amino-3-(6- n/a 0.123 0.286+++ fluoropyridin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 202 (R)-9-((5-(3-amino-3-(6- n/a n/a 0.264+++ ethylpyridin-2-yl)piperidin-1-yl)-2- (4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 203 (R)-9-((5-(3-amino-3-(6- n/a n/a 0.389+++ (difluoromethyl)pyridin-2- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 204(R)-9-((5-(3-amino-3-(6- n/a n/a n/a ++chloropyridin-2-yl)piperidin-1-yl)- 2-cyclopropylpyridin-4-yl)methyl)-9H-purin-6-amine 205 9-((5-(3-amino-3-(6-chloropyridin- n/a n/a 0.632+++ 2-yl)piperidin-1-yl)-2-(4- fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 206 (R)-2-(3-amino-1-(4-((6-amino- n/a 0.117 1.16 +++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-fluoropyridin- 4-ol 207(R)-9-((5-(3-amino-3-(5-fluoro-6- n/a n/a n/a ++methylpyridin-2-yl)piperidin-1-yl)- 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2086-(3-amino-1-(4-((6-amino-9H- n/a 2.78 n/a ++ purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)picolinonitrile 209(R)-9-((5-(3-amino-3-(5- n/a 0.324 n/a +++ (difluoromethoxy)pyridin-2-yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 210 9-((5-(3-amino-3-(6-chloropyridin- n/an/a n/a ++ 2-yl)piperidin-1-yl)-2- (imidazo[1,2-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6- amine 211 (R)-9-((5-(3-amino-3-(6-n/a 0.387 n/a +++ chloropyridin-2-yl)piperidin-1-yl)-2-(4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2129-((5-((R)-3-amino-3-(6-((R)-1- n/a 0.132 0.289 ++fluoroethyl)pyridin-2-yl)piperidin- 1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 213 (R)-9-((5-(3-amino-3-(6- n/a 0.258 0.387+++ chloropyridin-2-yl)piperidin-1-yl)- 2-(3-fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2146-(3-amino-1-(4-((6-amino-9H- n/a 0.444 2.426 ++purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoropyridin- 3-ol 2151-(6-((R)-3-amino-1-(4-((6-amino- n/a n/a n/a ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoropyridin- 3-yl)ethan-1-ol 216(R)-9-((5-(3-amino-3-(6-chloro-5- n/a 1.88 2.57 ++fluoropyridin-2-yl)piperidin-1 -yl)- 2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 217 (R)-6-(3-amino-1-(4-((6-amino- n/a 2.241n/a +++ 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)pyridin-2-ol 218 (R)-9-((5-(3-amino-3-(6- n/a 0.1011n/a ++ (difluoromethyl)-5-fluoropyridin-2- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 219(R)-2-(3-amino-1-(4-((6-amino- n/a 0.407 3.45 +++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-chloropyridin- 4-ol 2209-((5-(3-amino-3-(6-chloropyridin- n/a n/a n/a ++2-yl)piperidin-1-yl)-2-(1-methyl- 1H-benzo[d]imidazol-6-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 221 (R)-9-((5-(3-amino-3-(6-chloro-5- n/a0.269 1.29 +++ fluoropyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2229-((5-(3-amino-3-(6-chloropyridin- n/a n/a n/a ++2-yl)piperidin-1-yl)-2- (pyrazolo[1,5-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6- amine 2239-((5-(3-amino-3-(6-chloropyridin- n/a n/a n/a ++2-yl)piperidin-1-yl)-2- (pyrazolo[1,5-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6- amine 224 (R)-9-((5-(3-amino-3-(6-n/a 0.348 1.71 +++ chloropyridin-2-yl)piperidin-1-yl)-6′-fluoro-5′-methoxy-[2,2′- bipyridin]-4-yl)methyl)-9H-purin-6- amine225 9-((5-(3-amino-3-(6-chloropyridin- n/a 1.96 n/a ++2-yl)piperidin-1-yl)-2-(1-methyl- 1H-indazol-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 226 (R)-9-((5-(3-amino-3-(6- n/a 0.06680.169 +++ (fluoromethyl)pyridin-2- yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 227(R)-9-((5-(3-amino-3-(6- n/a 0.133 0.302 ++ (difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 228 9-((5-(3-amino-3-(6-chloropyridin- n/a0.611 n/a ++ 2-yl)piperidin-1-yl)-2-(4- (difluoromethoxy)-3-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 2299-((5-(3-amino-3-(6-chloropyridin- n/a 1.97 7.49 ++2-yl)piperidin-1-yl)-6′-methyl-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6- amine 230(R)-9-((5-(3-amino-3-(6-chloro-3- n/a 1.65 9.98 ++methoxypyridin-2-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 231 (R)-9-((5-(3-amino-3-(6- n/a 2.15 7.44++ chloropyridin-2-yl)piperidin-1-yl)- 5′-fluoro-6′-methoxy-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6- amine 232(R)-2-(3-amino-1-(4-((6-amino- n/a 1.47 7.65 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-methylpyridine 1-oxide 233 (R)-9-((5-(3-amino-3-(6-n/a 0.341 1.1 +++ chloropyridin-2-yl)piperidin-1-yl)- 2-(3,5-difluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2341-(6-((R)-3-amino-1-(4-((6-amino- n/a 1.62 5.99 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-chloropyridin- 3-yl)ethan-1-ol 235(R)-9-((5-(3-amino-3-(6-fluoro-4- n/a 0.705 0.97 +++methoxypyridin-2-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 236 (R)-9-((5-(3-amino-3-(6- n/a 1.39 6.30++ chloropyridin-2-yl)piperidin-1-yl)- 2-(2,6-difluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 237(R)-9-((5-(3-amino-3-(6- n/a 0.825 2.02 ++chloropyridin-2-yl)piperidin-1-yl)- 2-(2,6-difluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 238(R)-9-((5-(3-amino-3-(6- n/a 0.588 1.341 +++chloropyridin-2-yl)piperidin-1-yl)- 2-(2,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 239 (R)-2-(3-amino-1-(4-((6-amino- n/a 0.3531.54 +++ 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-fluoropyridin- 3-ol 2409-((5-(3-amino-3-(6-chloropyridin- n/a 0.821 5.93 ++2-yl)piperidin-1-yl)-5′,6′-difluoro- [2,3′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 241 (R)-9-((5-(3-amino-3-(5-fluoro-6- n/a 1.19 4.08 ++methylpyridin-2-yl)piperidin-1-yl)- 2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 242 (R)-9-((5-(3-amino-3-(6- n/a 2.714 8.19++ chloropyridin-2-yl)piperidin-1-yl)- 2-(2,3-difluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 243(R)-9-((5-(3-amino-3-(6- n/a 0.541 2.44 +++chloropyridin-2-yl)piperidin-1-yl)- 4′-fluoro-5′-methoxy-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6- amine 2445-(3-amino-3-(6-chloropyridin-2- n/a 12.5 33.3 ++yl)piperidin-1-yl)-4-((6-amino-9H- purin-9-yl)methyl)-5′-fluoro-[2,3′-bipyridin]-6′-ol 245 (S)-9-((5-(3-amino-3-(pyridin-4- n/a n/a 2.15 ++yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 246 (S)-9-((5-(3-amino-3-(2- n/a n/a 16.7 ++chloropyridin-4-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 247 (S)-9-((5-(3-amino-3-(2- n/a n/a 33.3 ++methylpyridin-4-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 248 (S)-9-((5-(3-amino-3-(3- n/a n/a 2.88 ++fluoropyridin-4-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 249 9-((5-(3-amino-3-(6- n/a n/a n/a +++chloropyridazin-3-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 250 (R)-9-((5-(3-amino-3-(6- n/a n/a n/a++ ethylpyrazin-2-yl)piperidin-1-yl)-2- (4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 251 (R)-9-((5-(3-amino-3-(2- n/a 0.440 1.52++ ethylpyrimidin-4-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 252 (R)-1-((5-(3-amino-3-(6- n/a n/a 7.25 ++ethylpyridin-2-yl)piperidin-1-yl)-2- cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 253 9-((5-(3-amino-3-(pyridazin-3- n/a0.357 n/a ++ yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 254 9-((5-(3-amino-3-(6- n/a n/a 1.54 ++chloropyrazin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 255 9-((5-(3-amino-3-(pyrimidin-4- n/a 0.232n/a ++ yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 256 (R)-1-((5-(3-amino-3-(6- n/a n/a n/a ++ethylpyrazin-2-yl)piperidin-1-yl)-2- (4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 257(R)-9-((5-(3-amino-3-(2- n/a 0.435 1.20 ++methylpyrimidin-4-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 258 (R)-9-((5-(3-amino-3-(6- n/a 0.434 n/a++ methylpyrazin-2-yl)piperidin-1-yl)- 2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 259 9-((5-(3-amino-3-(pyrazin-2- n/a n/a3.54 ++ yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 260 (R)-1-((5-(3-amino-3-(6- n/a n/a 1.52 ++(difluoromethyl)pyridin-2- yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine261 (R)-1-((5-(3-amino-3-(6- n/a n/a 0.235 +++methylpyridin-2-yl)piperidin-1-yl)- 2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 2621-((5-(3-amino-3-(6-fluoropyridin- n/a n/a 1.33 ++2-yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 263 1-((5-(3-amino-3-(6-n/a n/a 4.17 ++ methylpyridin-2-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)- 1H-imidazo[4,5-c]pyridin-4-amine 264(R)-1-((5-(3-amino-3-(6- n/a n/a 9.63 ++ (difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2- cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 265 1-((5-(3-amino-3-(6-chloropyridin-n/a n/a n/a + 2-yl)piperidin-1-yl)-2-(azetidin-1-yl)pyridin-4-yl)methyl)-1H- imidazo[4,5-c]pyridin-4-amine 2661-((5-(3-amino-3-(pyridin-2- n/a n/a 0.436 +++ yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 1H-imidazo[4,5-c]pyridin-4-amine 2671-((5-(3-amino-3-(6-chloropyridin- n/a n/a 1.91 ++2-yl)piperidin-1-yl)-2- cyclobutylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 268 1-((5-(3-amino-3-(6-chloropyridin- n/an/a n/a ++ 2-yl)piperidin-1-yl)-2- cyclobutylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 269 (S)-9-((5-(3-amino-3-(1-methyl- n/an/a 5.68 +++ 1H-pyrazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2701-((5-(3-amino-3-(1-methyl-1H- n/a n/a 15.3 ++pyrazol-4-yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 2719-((5-(3-amino-3-(pyridin-3- n/a n/a 33.3 + yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 272(S)-3-(3-amino-1-(4-((6-amino- n/a 1.746 10.5 +++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)pyridin-2(1H)-one 273 (R)-9-((5-(3-amino-3-(1- n/a n/an/a +++ (difluoromethyl)-1H-pyrazol-3- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 9H-purin-6-amine 274(R)-9-((5-(3-amino-3-(1-isopropyl- n/a n/a 5.54 +++1H-pyrazol-3-yl)piperidin-1-yl)-2- (4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 275 (R)-9-((5-(3-amino-3-(1-methyl- n/a n/an/a +++ 1H-pyrazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 276(R)-1-((5-(3-amino-3-(1-ethyl-1H- n/a n/a n/a ++pyrazo1-3-yl)piperidin-1-yl)-2- cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 277 1-((5-(3-amino-3-(1-ethyl-1H- n/an/a 2.20 ++ pyrazo1-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1 H-imidazo[4,5-c]pyridin-4-amine 2789-((5-(3-amino-3-(1-cyclopropyl- n/a n/a 0.475 +++1H-pyrazol-3-yl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 279 (R)-1-((5-(3-amino-3-(1- n/a n/a n/a +++(difluoromethyl)-1H-pyrazol-3- yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)- 1H-imidazo[4,5-c]pyridin-4-amine 2801-((5-(3-amino-3-(1-cyclopropyl- n/a n/a 1.49 +++1H-pyrazol-3-yl)piperidin-1-yl)-2- (4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5- c]pyridin-4-amine 2819-((5-(3-amino-3-(2-chlorothiazol- n/a 0.826 n/a ++4-yl)piperidin-1-yl)-2-(4- fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 282 9-((5-(3-amino-3-(1-methyl-1H- n/a 1.53 n/a ++1,2,3-triazol-4-yl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 283 (R)-9-((5-(3-amino-3-(2-methyl- n/a 0.111.02 +++ 2H-1,2,3-triazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin- 4-yl)methyl)-9H-purin-6-amine 284(R)-9-((5-(3-amino-3-(5- n/a 0.1108 0.254 +++methylisoxazol-3-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 285 (R)-2-((R)-3-amino-1-(4-((6- n/a0.0437 0.885 +++ amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-3-yl)-2-fluoroethan-1- ol286 (R)-2-((R)-3-amino-1-(4-((6- n/a 0.0059 0.655 +++amino-9H-purin-9-yl)methyl)-6- (2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoroethan-1- ol 287 9-((5-(3-amino-3-(1,2- n/an/a n/a ++ difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2889-((5-((R)-3-amino-3-((2R,6S)-6- n/a 2.39 5.72 ++methyl-1,4-dioxan-2-yl)piperidin- 1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2899-((5-((R)-3-amino-3-((R)-1,4- n/a 0.492 2.67 +++dioxan-2-yl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 290 9-((5-((R)-3-amino-3-((R)-1,4- n/a 0.4210.954 ++ dioxan-2-yl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2919-((5-((R)-3-amino-3-((R)-1,4- n/a 0.812 1.69 ++dioxan-2-yl)piperidin-1-yl)-2-(2- (difluoromethyl)-4,5-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 292(R)-7-(4-((6-amino-9H-purin-9- n/a n/a n/a ++ yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-oxa- 1,7-diazaspiro[4.5]decan-2-one 293(S)-9-((5-(3-amino-3-(1,1- n/a 1.3 3.21 ++difluoroprop-1-en-2-yl)piperidin-1- yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 294 9-((5-(3-amino-3-(2,2- n/a n/a 9.44 ++difluorovinyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 295 9-((5-(3-amino-3-(1- 2.332 n/a 1.86 ++fluoroethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 296 (R)-9-((5-(3-((1H-pyrazol-1- 0.336 n/a1.41 ++ yl)methyl)-3-aminopiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 2979-((5-(3-amino-3- 2.354 n/a n/a ++ ((methylthio)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin- 4-yl)methyl)-9H-purin-6-amine 2989-((5-(3-amino-3- n/a n/a n/a + ((methylsulfonyl)methyl)piperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 299(S)-1-((R)-3-amino-1-(4-((6- n/a 1.155 9.83 ++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2,2- trifluoroethan-1-ol 3009-((5-(3-amino-3-(1,2,2- n/a n/a n/a ++trifluoroethyl)piperidin-1-yl)-2- (3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 301 3-amino-1-(4-((6-amino-9H- n/a n/a n/a++ purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol 302 (3R,4R)-3-amino-1-(4-((6-amino-n/a n/a 0.563 ++ 9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(6- chloropyridin-2-yl)piperidin-4-ol 303(S)-9-((5-(3-amino-3-(2,2,2- 5.37 n/a n/a ++ trifluoroethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4- yl)methyl)-9H-purin-6-amine304 (S)-9-((5-(3-amino-3- n/a 0.101 0.592 ++ethynylpiperidin-1-yl)-2-(3,4- difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 305 (R)-9-((5-(3-amino-3- n/a 3.40 4.80 ++(difluoromethyl)piperidin-1-yl)-2- (3-fluoro-4- methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 306 9-((5-((3R,5R)-3-amino-5- n/a 6.46 n/a++ (fluoromethyl)piperidin-1-yl)-2-(3- fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 307 9-((5-((3S,5S)-3-amino-3-(2,2- n/a n/an/a + difluoroethyl)-5-methylpiperidin-1-yl)-2-(4-fluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 3089-((5-(3-amino-5- n/a n/a 27.5 ++ (methoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 3099-((5-((3R,5S)-3-amino-5- n/a n/a n/a ++ fluoropiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 3109-((5-((2S,5R)-5-amino-2- n/a n/a n/a + methylpiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 3119-((5-((2S,3R)-3-amino-2- n/a n/a n/a ++((difluoromethoxy)methyl)piperidin- 1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 312((2S,3R)-3-amino-1-(4-((6-amino- n/a n/a n/a ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-2-yl)methanol 313 9-((5-((2S,3R)-3-amino-2-((2,2- n/a n/an/a ++ difluoroethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin- 4-yl)methyl)-9H-purin-6-amine 3142-((2R,3R)-3-amino-1-(4-((6- n/a n/a n/a ++amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)ethan-1-ol 315 (2S,3R)-3-amino-1-(4-((6-amino- n/a n/an/a + 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)-N-methylpiperidine-2-carboxamide 316 (R)-1-((2S,3R)-3-amino-1-(4-((6- n/an/a n/a + amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)-2,2,2- trifluoroethan-1-ol 317(2S,3R)-3-amino-1-(4-((6-amino- n/a n/a n/a +9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)-N,N-dimethylpiperidine-2-carboxamide 318 (2S,3R)-3-amino-1-(4-((6-amino- n/an/a n/a + 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidine-2-carboxamide 319 (2S,3R)-3-amino-1-(4-((6-amino- n/a n/an/a + 9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidine-2-carboxamide 320 2-((2R,3R)-3-amino-1-(4-((6- n/a n/an/a + amino-9H-purin-9-yl)methyl)-6- (3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)acetamide 321 9-((2-(3,4-difluorophenyl)-5-(4- n/a n/an/a + oxa-1,8-diazaspiro[5.5]undecan-8-yl)pyridin-4-yl)methyl)-9H-purin- 6-amine 322(S)-3-(3-amino-1-(4-((6-amino- n/a n/a >33.70 ++9H-purin-9-yl)methyl)-6-(3,4- difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N- dimethylpropanamide 3239-((5-((2R,3R)-3-amino-2- n/a n/a n/a + phenylpiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4- yl)methyl)-9H-purin-6-amine 3243-amino-1-(4-((6-amino-9H-purin- n/a n/a n/a + 9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-2-one 325(R)-5-amino-1-(4-((6-amino-9H- n/a n/a n/a + purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3- yl)piperidin-2-one

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

The invention claimed is:
 1. A compound of Formula (I):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof; wherein: A is N or CR⁹ wherein R⁹ is hydrogenor halo; L is a bond; R¹ is H; or R¹ and R² together with NH forms a 5-8membered heterocyclyl containing 1-2 heteroatoms selected from N, O andS as ring members; wherein said 5-8 membered heterocyclyl isunsubstituted or substituted by an oxo substituent; R² is selected fromthe group consisting of: (i) hydrogen, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl,-hydroxyC₁₋₆ alkylene, -hydroxyhaloC₁₋₆ alkylene,—C₁₋₆alkoxyC₁₋₆alkylene, -haloC₁₋₆ alkoxyC₁₋₆ alkylene or —C₃₋₈cycloalkoxy(C₁₋₆ alkyl); (ii) cyano; -cyanoC₁₋₆ alkylene; —C₁₋₆alkylthioC₁₋₆alkyl; —C₂₋₆ alkenyl; -haloC₂₋₆ alkenyl; —C₂₋₆ alkynyl;—C₁₋₄ alkylSOC₁₋₄alkyl; —C₁₋₄ alkylSO₂C₁₋₄alkyl; —SO₂R⁸ or —C(C₁₋₄alkyl)=N—O(C₁₋₄ alkyl); (iii) —C₁₋₄alkylcarbonyl;—(CR^(a)R^(b))_(p)—C(═O)—OR¹⁰; or —C(═O)—(CR^(a)R^(b))_(q)R¹¹; whereinR¹¹ is C₃₋₇ cycloalkyl, 5-6 membered heterocyclyl or 5-6 memberedheteroaryl, each of which is independently unsubstituted or substitutedwith C₁₋₆ alkyl or C₁₋₆ alkoxy; (iv) —(CR^(a)R^(b))_(r)—C(═O)—NR¹²R¹³wherein R¹² is hydrogen or C₁₋₆ alkyl; R¹³ is hydrogen, —C₁₋₆ alkyl or a5-6 membered heterocyclic ring; or R¹² and R¹³ together form a 5-6membered heterocyclic ring; wherein said 5-6 membered heterocyclic ringis unsubstituted or substituted with C₁₋₄ alkyl; (v) 5-6 memberedheterocyclylC₀₋₆alkyl or 5-6 membered heterocyclyl(haloC₁₋₄ alkyl)wherein each said heterocyclyl radical is unsubstituted or substitutedby oxo; and (vi) 5-9 membered heteroarylC₀₋₆alkyl or 5-9 memberedheteroaryl(haloC₁₋₄alkyl), wherein each said heteroaryl radical isunsubstituted or substituted by —C₁₋₄ alkyl, -haloC₁₋₄ alkyl,-hydroxyC₁₋₄ alkylene, —C₁₋₄ alkoxy,-haloC₁₋₄ alkoxy, halo, hydroxy,cyano, oxido, -aminocarbonylC₀₋₆alkyl, —C₁₋₄alkylaminocarbonylC₀₋₆alkyl,-diC₁₋₄alkylaminocarbonylC₀₋₆alkyl or —C₃₋₇ cycloalkyl; R^(3a), R^(3b),R^(4a), and R^(4b) are independently hydrogen, halo, cyano, hydroxyl,—C₁₋₆ alkyl, -haloC₁₋₆ alkyl, -hydroxyC₁₋₆ alkylene, —C₁₋₆ alkoxy, or—C₁₋₆alkoxyC₁₋₆alkylene; R^(5a) and R^(5b) are independently hydrogen or—C₁₋₆ alkyl: R^(6a) and R^(6b) are independently hydrogen, —C₁₋₆ alkyl,-hydroxyC₁₋₆ alkylene, —C₁₋₆alkoxyC₁₋₆alkylene, -haloC₁₋₆ alkoxyC₁₋₆alkylene, -hydroxyhaloC₁₋₆ alkylene, aryl, —C(═O)—OR¹⁴, or—(CR^(a)R^(b))_(s)—C(═O)—NR¹⁵R¹⁶; or R^(3a) and R^(3b), R^(4a) andR^(4b), R^(5a) and R^(5b) or R^(6a) and R^(6b) forms an oxo substituent;R⁷ is H, —C₁₋₄ alkoxy, halo or C₁₋₄ alkyl; R⁸ is C₃₋₈ cycloalkyl(C₀₋₆alkyl); 4-6 membered heterocyclylC₀₋₆alkyl comprising 1-3 heteroatomsselected from N, O and S; aryl or 5-9 membered heteroarylC₀₋₆alkylcomprising 1-3 heteroatoms selected from N, O and S; wherein R⁸ isunsubstituted or substituted by 1-3 R¹⁷; R¹⁷ is halo, hydroxy, cyano,—C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy, -haloC₁₋₆ alkoxy,—NR^(a)C(═O)CR^(c)═C(R^(c))₂ or —(CR^(a)R^(b))_(t)—NR^(a)—C(═O)—R¹⁸;R^(a), R^(b), R^(c), R¹⁰, R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen or—C₁₋₄ alkyl; R¹⁸ is —C₁₋₄ alkyl or —C₁₋₄haloalkyl; and p, q, r, s and tare independently 0-4.
 2. The compound of Formula (I) in claim 1 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein A is N.
 3. The compound of Formula (I) in claim 2,or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt; wherein R^(3a) is hydrogen or halo; and R^(3b) ishydrogen, halo, -hydroxyl, —C₁₋₆ alkoxy or cyano; or R^(4a) is hydrogenor halo; and R^(4b) is hydrogen, halo, —C₁₋₆alkoxyC₁₋₆alkylene, —C₁₋₆alkyl or -haloC₁₋₆ alkyl; or R^(5a) is hydrogen and R^(5b) is hydrogenor —C₁₋₆ alkyl; or R^(5a) and R^(5b) together form an oxo substituent.4. The compound of Formula (I) in claim 2 or an enantiomer, anenantiomeric mixture, or a pharmaceutically acceptable salt; wherein:R^(6a) is hydrogen; R^(6b) is hydrogen, -haloC₁₋₆ alkoxyC₁₋₆ alkylene,-hydroxyC₁₋₆ alkylene, -hydroxyhaloC₁₋₆ alkylene, carboxyl, phenyl or—(CR^(a)R^(b))_(t)—C(O)—NR¹⁵R¹⁶; R^(a), R^(b), R¹⁵ and R¹⁶ areindependently hydrogen or —C₁₋₄ alkyl; and t is 0-1; or R^(6a) andR^(6b) together form an oxo substituent.
 5. The compound of Formula (I)in claim 3 or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein R⁷ is H, —C₁₋₄ alkoxyor halo.
 6. The compound of Formula (I) in claim 2 or a pharmaceuticallyacceptable salt thereof; wherein R¹, R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), R^(6a), R^(6b) and R⁷ are hydrogen.
 7. The compound ofFormula (I) in claim 1, wherein said compound is a compound of Formula(II):

or an enantiomer, an enantiomeric mixture, or a pharmaceuticallyacceptable salt thereof.
 8. The compound according to claim 7 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, -hydroxyC₁₋₆alkylene, -hydroxyhaloC₁₋₆ alkylene, —C₁₋₆alkoxyC₁₋₆alkylene, -haloC₁₋₆alkoxyC₁₋₆ alkylene or —C₃₋₈ cycloalkoxy(C₁₋₆ alkyl).
 9. The compoundaccording to claim 7 or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein R² is2,2-difluoroethyl; 2-methyl-propan-1-olyl; ethan-1-olyl;2,2-difluoroethan-1-olyl; 2-fluoroethan-1-olyl;2,2,2-trifluoroethan-1-olyl; difluoromethoxyl; or2,2,2-trifluoroethoxyl.
 10. The compound according to claim 2 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is 2,2-difluoroethyl; 2-methyl-propan-1-olyl;ethan-1-olyl; 2,2-difluoroethan-1-olyl; 2-fluoroethan-1-olyl;2,2,2-trifluoroethan-1-olyl; difluoromethoxyl; or2,2,2-trifluoroethoxyl.
 11. The compound according to claim 7 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R² is


12. The compound according to claim 7 or an enantiomer, an enantiomericmixture, or a pharmaceutically acceptable salt thereof; wherein R⁸ isphenyl substituted with 1-3 R¹⁷; R¹⁷ is halo, hydroxy, cyano, —C₁₋₆alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy, -haloC₁₋₆ alkoxy,—NR^(d)C(O)CR^(d)═C(R^(d))₂ or —(CR^(a)R^(b))_(t)—NR^(d)—C(O)—R¹⁸;R^(a), R^(b) and R^(d) are independently hydrogen or —C₁₋₄ alkyl; R¹⁸ isC₁₋₄haloalkyl; and t is 0-1.
 13. The compound according to claim 2 or anenantiomer, an enantiomeric mixture, or a pharmaceutically acceptablesalt thereof; wherein R⁸ is phenyl substituted with 1-3 R¹⁷; R¹⁷ ishalo, hydroxy, cyano, —C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy,-haloC₁₋₆ alkoxy, —NR^(d)C(O)CR^(d)═C(R^(d))₂ or—(CR^(a)R^(b))_(t)—NR^(d)—C(O)—R¹⁸; R^(a), R^(b) and R^(d) areindependently hydrogen or —C₁₋₄ alkyl; R¹⁸ is C₁₋₄haloalkyl; and t is0-1.
 14. The compound according to claim 9 or an enantiomer, anenantiomeric mixture, or a pharmaceutically acceptable salt thereof;wherein R⁸ is phenyl substituted with 1-3 R¹⁷; and R¹⁷ is halo, hydroxy,—C₁₋₆ alkyl, -haloC₁₋₆ alkyl, —C₁₋₆ alkoxy or -haloC₁₋₆ alkoxy.
 15. Thecompound according to claim 2 or an enantiomer, an enantiomeric mixture,or a pharmaceutically acceptable salt thereof; wherein R⁸ is phenylsubstituted with 1-3 R¹⁷; and R¹⁷ is halo, hydroxy, —C₁₋₆ alkyl,-haloC₁₋₆ alkyl, —C₁₋₆ alkoxy or -haloC₁₋₆ alkoxy.
 16. The compoundaccording to claim 1 or an enantiomer, an enantiomeric mixture, or apharmaceutically acceptable salt thereof; wherein said compound isselected from a compound in the following table, or a pharmaceuticallyacceptable salt thereof: Ex No. Chemical Name 1(R)-9-((5-(3-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 29-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(2-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3(3S,4R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-4-ol 4(R)-9-((5-(3-aminopiperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 59-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 6(R)-9-((5-(3-aminopiperidin-1-yl)-2-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 7(R)-4-(4-((6-amino-9H-purin-9-yl)methyl)-5-(3-aminopiperidin-1-yl)pyridin-2-yl)-2-chlorobenzonitrile 89-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 94-(5-((2S,3R)-3-amino-2-(methoxymethyl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)-2-fluorobenzonitrile 109-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 11(R)-9-((5-(3-aminopiperidin-1-yl)-2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 129-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(3-chlorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 134-(5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)-2-fluorobenzonitrile 149-((5-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-2-(2,3-dihydrobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 159-((5-(3-amino-4-methoxypiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 16(R)-9-((5-(5-amino-3,3-difluoropiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 179-((5-(3-amino-4,4-difluoropiperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 183-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidine-4-carbonitrile 19(R)-1-((5-(3-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-7-chloro-1H-imidazo[4,5-c]pyridin-4-amine 20(R)-9-((5-(3-amino-3-methylpiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 21(R)-1-((5-(3-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 22(R)-9-((5-(3-amino-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 23(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 24(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 25(R)-9-((5-(3-amino-3-(isopropoxymethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 26(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(5-chloro-2-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 27(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3-chlorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 28(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3-chloro-4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 29(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(2,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 30(R)-9-((5-(3-amino-3-(cyclobutoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 31(R)-9-((5-(3-amino-3-(cyclopropoxymethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 32(R)-9-((5-(3-amino-3-(cyclobutoxymethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 33(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 34(R)-9-((5-(3-amino-3-(isopropoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 35(R)-9-((5-(3-amino-3-(cyclobutoxymethyl)piperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 36(R)-9-((5-(3-amino-3-(cyclobutoxymethyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 37(R)-9-((5-(3-amino-3-(isopropoxymethyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 38(R)-9-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 39(R)-9-((5-(3-amino-3-((2,2,2-trifluoroethoxy)methyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 40(R)-9-((5-(3-amino-3-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 41(R)-9-((5-(3-amino-3-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 42(R)-9-((5-(3-amino-3-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 43(R)-9-((5-(3-amino-3-((2,2,2-trifluoroethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 44(R)-9-((5-(3-amino-3-((difluoromethoxy)methyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 45(R)-9-((5-(3-amino-3-((2,2,2-trifluoroethoxy)methyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 46(R)-1-((5-(3-amino-3-(methoxymethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 47(S)-9-((5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 48(S)-1-((5-(3-amino-3-(thiazol-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 49(S)-1-((5-(3-amino-3-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 50(S)-1-((5-(3-amino-3-(pyridin-2-ylmethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 51(S)-1-((5-(3-amino-3-(pyridin-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 52(S)-9-((5-(3-amino-3-(oxazol-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 53(S)-9-((5-(3-amino-3-(thiazol-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 54(S)-9-((5-(3-amino-3-(pyridin-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 55(S)-9-((5-(3-amino-3-((6-methylpyridin-2-yl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 56(S)-9-((5-(3-amino-3-((l-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 57(S)-1-((5-(3-amino-3-(thiazol-2-ylmethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 58(S)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)acetic acid 59(S)-2-(3-amino-1-(4-((4-amino-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N-dimethylacetamide 609-((5-(3-amino-3-(2-methoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 61(S)-9-((5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 62(S)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)acetamide 63(S)-1-((5-(3-amino-3-(oxazol-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 64N-(4-(5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)phenyl)-3-bromopropanamide 659-((5-((S)-3-amino-3-((R)-1-(pyridin-2-yl)ethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 662-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-N-methylacetamide 672-(3-amino-1-(4-((4-amino-7-chloro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N-methylacetamide 682-(3-amino-1-(4-((4-amino-7-chloro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N-dimethylacetamide699-((5-(3-amino-3-((6-fluoropyridin-2-yl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 70(S)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N-dimethylacetamide 71(S)-9-((5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 722-(3-amino-1-(4-((4-amino-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N-methylacetamide 73 methyl(S)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)acetate 74(S)-9-((5-(3-amino-3-(pyrazin-2-ylmethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 75N-(4-(5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)benzyl)-2-chloroacetamide 76N-(4-(5-(3-amino-3-(2,2-difluoroethyl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)phenyl)acrylamide 772-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)acetonitrile 78(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)-N-methylpiperidine-3-carboxamide 79 methyl(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluorophenyl)pyridin-3-yl)piperidine-3-carboxylate 80(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)-N,N-dimethylpiperidine-3-carboxamide 81isopropyl(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidine-3-carboxylate 82(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide 83 tert-butyl(R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidine-3-carboxylate 84(R)-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone 853-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)piperidine-3-carboxamide 86(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(piperidin-1-yl)methanone 87(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(2-methylpiperidin-1-yl)methanone88 (3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(2-methylpyrrolidin-1-yl)methanone 89 1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,3-dimethylbutan-1-one 90(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-ol 919-((5-((R)-3-amino-3-((S)-fluoro(pyridin-2-yl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 92(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-ol 939-((5-((R)-3-amino-3-((S)-1-methoxyethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 949-((5-((R)-3-amino-3-((R)-1-methoxyethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 959-((5-((R)-3-amino-3-((S)-1-methoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 96(E)-1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)ethan-1-one O-methyl oxime 979-((5-((R)-3-amino-3-((R)-1-methoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 98(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylpropan-1-ol 999-((5-(3-amino-3-((R)-1-ethoxyethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 100(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(cyclopentyl)methanone 101(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylbutan-1-one 102(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylbutan-1-one 1031-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-cyclopropylpropan-1-one104 (R)-1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-methylpropan-1-one 105(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(cyclobutyl)methanone 106(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(3-methoxycyclopentyl)methanone107 (3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(1-methylcyclopropyl)methanone108 (3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(tetrahydro-2H-pyran-4-yl)methanone 109(R)-1-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-dimethylpropan-1-one 110(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(1-methyl-1H-pyrazol-3-yl)methanone 111 (3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(tetrahydrofuran-3-yl)methanone112 (3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)(3-methyloxetan-3-yl)methanone113 (R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or114 (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 115(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2-methylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 116(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 117(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4,5-difluoro-2-methylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 118(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)-5-methoxypyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol119 (R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 120(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 121(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 122(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-chloro-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 123(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(6-fluoro-1-methyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol124(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-chloro-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 125(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 126(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4-dimethylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 127(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 128(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-2,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 129(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-5-fluoro-2-methylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 130(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-cyclohexylpyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 131(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 132(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 133(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-chloro-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 134(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 135(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-5-fluoro-6-(2-fluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol136(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(1,6-dimethyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 137(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 138(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 139(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-chloro-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 140(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethyl)-2-methylphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 141(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol142 (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4-difluorophenyl)-5-fluoropyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol143(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(6-fluoro-1-methyl-1H-indazol-5-yl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol1444-(5-((R)-3-amino-3-((S)-2,2-difluoro-1-hydroxyethyl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)pyridin-2-yl)-2,5-difluorophenol 145(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-cyclohexylpyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 146(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 147(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 148(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-chloro-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 149(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)-5-fluoropyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol150 (R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-2,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 151(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 152(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-chloro-3-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 153(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-(difluoromethoxy)-2-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 154(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3-(difluoromethyl)-2,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 155(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 156(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or157 (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 158(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or 159(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-fluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 160(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or161(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 162(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or 163(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 164(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or165(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 166(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol;or 167(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol168(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or169(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-chloro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 170(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or 171(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 172(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,3,4-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 173(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or174(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 175(S)-1-((R)-3-amino-1-(44(6-amino-9H-purin-9-yl)methyl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol; or 176(R)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-5-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol 1779-((5-(3-amino-3-(6-methylpyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 178(R)-9-((5-(3-amino-3-(6-methoxypyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 1799-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(1,3-dihydroisobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 180(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-5′-chloro-6′-fluoro-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 181(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 182(R)-9-((5-(3-amino-3-(6-cyclopropylpyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 1839-((5-((R)-3-amino-3-(6-((S)-1-fluoroethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 1849-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(4-(difluoromethoxy)phenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 185(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,3-dihydrobenzofuran-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 1869-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(benzo[d][1,3[dioxol-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 187(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 188(R)-9-((5-(3-amino-3-(6-chloro-5-fluoropyridin-2-yl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 1899-((5-(3-amino-3-(5-fluoropyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 190(R)-9-((5-(3-amino-3-(5-fluoro-6-methylpyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 191(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-6′-chloro-5′-fluoro-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 192(R)-9-((5-(3-amino-3-(6-chloro-3-fluoropyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 1939-((5-(3-amino-3-(5-fluoro-6-(fluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 194(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-6′-chloro-5′-methoxy-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 1956-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)picolinamide 196(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-5′-fluoro-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 197(R)-9-((5-(3-amino-3-(6-(1,1-difluoroethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 198(R)-9-((5-(3-amino-3-(pyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 199(R)-9-((5-(3-amino-3-(3-fluoropyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 200(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 201(R)-9-((5-(3-amino-3-(6-fluoropyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 202(R)-9-((5-(3-amino-3-(6-ethylpyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 203(R)-9-((5-(3-amino-3-(6-(difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 204(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)-9H-purin-6-amine 2059-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 206(R)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-fluoropyridin-4-ol 207(R)-9-((5-(3-amino-3-(5-fluoro-6-methylpyridin-2-yl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2086-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)picolinonitrile 209(R)-9-((5-(3-amino-3-(5-(difluoromethoxy)pyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2109-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(imidazo[1,2-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 211(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2129-((5-((R)-3-amino-3-(6-((R)-1-fluoroethyl)pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 213(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2146-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoropyridin-3-01 2151-(6-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoropyridin-3-yl)ethan-1-ol216(R)-9-((5-(3-amino-3-(6-chloro-5-fluoropyridin-2-yl)piperidin-1-yl)-2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 217(R)-6-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)pyridin-2-ol 218(R)-9-((5-(3-amino-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 219(R)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-chloropyridin-4-ol 2209-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(1-methyl-1H-benzo[d[imidazol-6-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 221(R)-9-((5-(3-amino-3-(6-chloro-5-fluoropyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2229-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(pyrazolo[1,5-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 2239-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(pyrazolo[1,5-a]pyridin-6-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 224(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-6′-fluoro-5′-methoxy-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 2259-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 226(R)-9-((5-(3-amino-3-(6-(fluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 227(R)-9-((5-(3-amino-3-(6-(difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2289-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(4-(difluoromethoxy)-3-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine2299-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-6′-methyl-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 230(R)-9-((5-(3-amino-3-(6-chloro-3-methoxypyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 231(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-5′-fluoro-6′-methoxy-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 232(R)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-methylpyridine 1-oxide 233(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(3,5-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2341-(6-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-chloropyridin-3-yl)ethan-1-ol235(R)-9-((5-(3-amino-3-(6-fluoro-4-methoxypyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 236(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,6-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 237(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,6-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 238(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 239(R)-2-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-6-fluoropyridin-3-01 2409-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-5′,6′-difluoro-[2,3′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 241(R)-9-((5-(3-amino-3-(5-fluoro-6-methylpyridin-2-yl)piperidin-1-yl)-2-(4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 242(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(2,3-difluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 243(R)-9-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-4′-fluoro-5′-methoxy-[2,2′-bipyridin]-4-yl)methyl)-9H-purin-6-amine 2445-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-4-((6-amino-9H-purin-9-yl)methyl)-5′-fluoro-[2,3′-bipyridin]-6′-ol 245(S)-9-((5-(3-amino-3-(pyridin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 246(S)-9-((5-(3-amino-3-(2-chloropyridin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 247(S)-9-((5-(3-amino-3-(2-methylpyridin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 248(S)-9-((5-(3-amino-3-(3-fluoropyridin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2499-((5-(3-amino-3-(6-chloropyridazin-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 250(R)-9-((5-(3-amino-3-(6-ethylpyrazin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 251(R)-9-((5-(3-amino-3-(2-ethylpyrimidin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 252(R)-1-((5-(3-amino-3-(6-ethylpyridin-2-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2539-((5-(3-amino-3-(pyridazin-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2549-((5-(3-amino-3-(6-chloropyrazin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2559-((5-(3-amino-3-(pyrimidin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 256(R)-1-((5-(3-amino-3-(6-ethylpyrazin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 257(R)-9-((5-(3-amino-3-(2-methylpyrimidin-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 258(R)-9-((5-(3-amino-3-(6-methylpyrazin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2599-((5-(3-amino-3-(pyrazin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 260(R)-1-((5-(3-amino-3-(6-(difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 261(R)-1-((5-(3-amino-3-(6-methylpyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2621-((5-(3-amino-3-(6-fluoropyridin-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2631-((5-(3-amino-3-(6-methylpyridin-2-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 264(R)-1-((5-(3-amino-3-(6-(difluoromethyl)pyridin-2-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2651-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-(azetidin-1-yl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2661-((5-(3-amino-3-(pyridin-2-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2671-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-cyclobutylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2681-((5-(3-amino-3-(6-chloropyridin-2-yl)piperidin-1-yl)-2-cyclobutylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 269(S)-9-((5-(3-amino-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2701-((5-(3-amino-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2719-((5-(3-amino-3-(pyridin-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 272(S)-3-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)pyridin-2(1H)-one 273(R)-9-((5-(3-amino-3-(1-(difluoromethyl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 274(R)-9-((5-(3-amino-3-(1-isopropyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 275(R)-9-((5-(3-amino-3-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 276(R)-1-((5-(3-amino-3-(1-ethyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-cyclopropylpyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2771-((5-(3-amino-3-(1-ethyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2789-((5-(3-amino-3-(1-cyclopropyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 279(R)-1-((5-(3-amino-3-(1-(difluoromethyl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine2801-((5-(3-amino-3-(1-cyclopropyl-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-4-amine 2819-((5-(3-amino-3-(2-chlorothiazol-4-yl)piperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2829-((5-(3-amino-3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 283(R)-9-((5-(3-amino-3-(2-methyl-2H-1,2,3-triazol-4-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 284(R)-9-((5-(3-amino-3-(5-methylisoxazol-3-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 285(R)-2-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoroethan-1-ol 286(R)-2-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,4,5-trifluorophenyl)pyridin-3-yl)piperidin-3-yl)-2-fluoroethan-1-ol 2879-((5-(3-amino-3-(1,2-difluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2889-((5-((R)-3-amino-3-((2R,6S)-6-methyl-1,4-dioxan-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2899-((5-((R)-3-amino-3-((R)-1,4-dioxan-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2909-((5-((R)-3-amino-3-((R)-1,4-dioxan-2-yl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2919-((5-((R)-3-amino-3-((R)-1,4-dioxan-2-yl)piperidin-1-yl)-2-(2-(difluoromethyl)-4,5-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine292(R)-7-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3 -yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one 293(S)-9-((5-(3-amino-3-(1,1-difluoroprop-1-en-2-yl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2949-((5-(3-amino-3-(2,2-difluorovinyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2959-((5-(3-amino-3-(1-fluoroethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 296(R)-9-((5-(3-((1H-pyrazol-1-yl)methyl)-3-aminopiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2979-((5-(3-amino-3-((methylthio)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 2989-((5-(3-amino-3-((methylsulfonyl)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 299(S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-2,2,2-trifluoroethan-1-ol300 9-((5-(3-amino-3-(1,2,2-trifluoroethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3013-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(2,2-difluoroethyl)piperidin-4-ol 302(3R,4R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-3-(6-chloropyridin-2-yl)piperidin-4-ol 303(S)-9-((5-(3-amino-3-(2,2,2-trifluoroethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 304(S)-9-((5-(3-amino-3-ethynylpiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 305(R)-9-((5-(3-amino-3-(difluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3069-((5-((3R,5R)-3-amino-5-(fluoromethyl)piperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3079-((5-((35,55)-3-amino-3-(2,2-difluoroethyl)-5-methylpiperidin-1-yl)-2-(4-fluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3089-((5-(3-amino-5-(methoxymethyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3099-((5-((3R,5S)-3-amino-5-fluoropiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3109-((5-((2S,5R)-5-amino-2-methylpiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3119-((5-((2S,3R)-3-amino-2-((difluoromethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 312((2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)methanol 3139-((5-((2S,3R)-3-amino-2-((2,2-difluoroethoxy)methyl)piperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3142-((2R,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)ethan-1-ol 315(2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-N-methylpiperidine-2-carboxamide 316(R)-1-((2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)-2,2,2-trifluoroethan-1-ol317 (2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)-N,N-dimethylpiperidine-2-carboxamide 318(2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidine-2-carboxamide 319(2S,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidine-2-carboxamide 3202-((2R,3R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-yl)acetamide 3219-((2-(3,4-difluorophenyl)-5-(4-oxa-1,8-diazaspiro[5.5]undecan-8-yl)pyridin-4-yl)methyl)-9H-purin-6-amine 322(S)-3-(3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-3-yl)-N,N-dimethylpropanamide 3239-((5-((2R,3R)-3-amino-2-phenylpiperidin-1-yl)-2-(3,4-difluorophenyl)pyridin-4-yl)methyl)-9H-purin-6-amine 3243-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-one 325(R)-5-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(3,4-difluorophenyl)pyridin-3-yl)piperidin-2-one


17. The compound according to claim 1 or an enantiomer, an enantiomericmixture, or a pharmaceutically acceptable salt thereof; wherein saidcompound has the following formula or a pharmaceutically acceptable saltthereof:


18. The compound according to claim 1 or an enantiomer, an enantiomericmixture, or a pharmaceutically acceptable salt thereof; wherein saidcompound has the following formula or a pharmaceutically acceptable saltthereof:


19. A compound having the following formula or a pharmaceuticallyacceptable salt thereof:


20. The compound of claim 19, wherein the compound has the formula:


21. A compound having the following formula or a pharmaceuticallyacceptable salt thereof:


22. The compound of claim 21, wherein the compound has the formula:


23. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carrier.
 24. A pharmaceutical compositioncomprising a compound according to claim 7 or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarrier.
 25. A pharmaceutical composition comprising a compoundaccording to claim 19 or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable carrier.
 26. A pharmaceuticalcomposition comprising a compound according to claim 21 or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carrier.
 27. A pharmaceutical compositioncomprising a compound according to claim 22, and one or morepharmaceutically acceptable carrier.
 28. A method for treating a diseaseor condition mediated by nuclear SET domain-containing protein 2 (NSD2),comprising administering to a subject in need of such treatment atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein the disease orcondition mediated by NSD2 is breast cancer, cervical cancer, skincancer, ovarian cancer, gastric cancer, prostate cancer, pancreaticcancer, lung cancer, hepatocellular carcinoma, head and neck cancer,peripheral nerve sheath tumor, osteosarcoma, multiple myeloma,neuroblastoma, leukemia, or non-Hodgkin's lymphoma.
 29. The method ofclaim 28, wherein said disease or condition mediated by NSD2 is breastcancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer,prostate cancer, pancreatic cancer, lung cancer, hepatocellularcarcinoma, multiple myeloma, leukemia, or non-Hodgkin's lymphoma.